Bone marrow secreted proteins and polynucleotides

ABSTRACT

Novel polynucleotides and secreted proteins encoded thereby are disclosed. The proteins can be used as therapeutics, for example, to stimulate blood cell generation in patients receiving cancer chemotherapy, to treat bone marrow transplantation patients, and to heal fractured bones. Polynucleotides of the invention can be used therapeutically, to provide proteins of the invention. Polynucleotides of the invention can also be used diagnostically, such as on polynucleotide arrays, to detect differential gene expression in diseased tissue compared with gene expression in normal tissue.

[0001] This application claims the benefit of co-pending provisional applications Ser. No. 60/068,958, filed Dec. 30, 1997, Ser. No. 60/101,603, filed Sep. 24, 1998, and Ser. No. 60/102,540 filed Sep. 30, 1998, which are incorporated herein by reference.

TECHNICAL AREA OF THE INVENTION

[0002] This invention relates to proteins secreted from bone marrow and to polynucleotides encoding the secreted proteins. The invention also relates to therapeutic and diagnostic utilities for the polynucleotides and proteins.

BACKGROUND OF THE INVENTION

[0003] Bone marrow stromal cells secrete a variety of protein factors required for the formation of blood and bone cells and for other physiological processes. Known regulatory factors involved in hematopoiesis and/or bone development include SCF, IL-3, IL-6, GM-CSF, M-CSF, EPO, TPO, bone morphogenic proteins, erythroid potentiating factor, and TGF-β. However, it is believed that additional secreted protein factors which control hematopoiesis and bone morphogenesis remain to be identified.

SUMMARY OF THE INVENTION

[0004] It is an object of the invention to provide proteins secreted from bone marrow stromal cells and polynucleotides encoding the secreted proteins. These and other objects of the invention are provided by one or more of the embodiments described below.

[0005] One embodiment of the invention is an isolated and purified protein comprising an amino acid sequence which is at least 85% identical to an amino acid sequence selected from the group consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and 44. Percent identity is determined using a Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 1.

[0006] Another embodiment of the invention is an isolated and purified protein comprising an amino acid sequence selected from the group consisting of at least 95 contiguous amino acids of SEQ ID NO:2, at least 101 contiguous amino acids of SEQ ID NO:4, at least 14 contiguous amino acids selected from amino acids 1-312 of SEQ ID NO:6, at least 179 contiguous amino acids of SEQ ID NO:6, at least 75 contiguous amino acids of SEQ ID NO:6, at least 179 contiguous amino acids of SEQ ID NO:8, at least 136 contiguous amino acids of SEQ ID NO:8, at least 17 contiguous amino acids selected from amino acids 1-287 of SEQ ID NO:8, at least 82 contiguous amino acids of SEQ ID NO:10, at least 31 contiguous amino acids selected from amino acids 1-238 of SEQ ID NO:10, at least 96 contiguous amino acids of SEQ ID NO:12, at least 27 contiguous amino acids selected from amino acids 250-383 of SEQ ID NO:12, at least 6 contiguous amino acids selected from amino acids 1-184 of SEQ ID NO:12, at least 8 contiguous amino acids selected from amino acids 268-364 of SEQ ID NO:12, at least 104 contiguous amino acids of SEQ ID NO:14, at least 75 contiguous amino acids of SEQ ID NO:14, at least 17 contiguous amino acids selected from amino acids 1-150 of SEQ ID NO:14, at least 6 contiguous amino acids selected from amino acids 204-261 of SEQ ID NO:14, at least 6 contiguous amino acids selected from amino acids 1-111 of SEQ ID NO:14, at least 8 contiguous amino acids of SEQ ID NO:16, at least 46 contiguous amino acids of SEQ ID NO:18, at least 39 contiguous amino acids selected from amino acids 13-232 of SEQ ID NO:18, at least 6 contiguous amino acids of SEQ ID NO:20, at least 7 contiguous amino acids of SEQ ID NO:22, at least 7 contiguous amino acids of SEQ ID NO:24, at least 11 contiguous amino acids of SEQ ID NO:26, at least 257 contiguous amino acids of SEQ ID NO:28, at least 6 contiguous amino acids selected from amino acids 1-31 of SEQ ID NO:28, at least 6 contiguous amino acids of SEQ ID NO:30, at least 117 contiguous amino acids of SEQ ID NO:32, at least 6 contiguous amino acids selected from amino acids 1-65 of SEQ ID NO:32, at least 6 contiguous amino acids of SEQ ID NO:34, at least 14 contiguous amino acids of SEQ ID NO:36, at least 19 contiguous amino acids of SEQ ID NO:38, at least 8 contiguous amino acids of SEQ ID NO:40, at least 7 contiguous amino acids of SEQ ID NO:42, and at least 10 contiguous amino acids of SEQ ID NO:44.

[0007] Still another embodiment of the invention is a fusion protein comprising two protein segments joined together with a peptide bond. The first protein segment consists of an amino acid sequence selected from the group consisting of at least 95 contiguous amino acids of SEQ ID NO:2, at least 101 contiguous amino acids of SEQ ID NO:4, at least 14 contiguous amino acids selected from amino acids 1-312 of SEQ ID NO:6, at least 179 contiguous amino acids of SEQ ID NO:6, at least 75 contiguous amino acids of SEQ ID NO:6, at least 179 contiguous amino acids of SEQ ID NO:8, at least 136 contiguous amino acids of SEQ ID NO:8, at least 17 contiguous amino acids selected from amino acids 1-287 of SEQ ID NO:8, at least 82 contiguous amino acids of SEQ ID NO:10, at least 31 contiguous amino acids selected from amino acids 1-238 of SEQ ID NO:10, at least 96 contiguous amino acids of SEQ ID NO:12, at least 27 contiguous amino acids selected from amino acids 250-383 of SEQ ID NO:12, at least 6 contiguous amino acids selected from amino acids 1-184 of SEQ ID NO:12, at least 8 contiguous amino acids selected from amino acids 268-364 of SEQ ID NO:12, at least 104 contiguous amino acids of SEQ ID NO:14, at least 75 contiguous amino acids of SEQ ID NO:14, at least 17 contiguous amino acids selected from amino acids 1-150 of SEQ ID NO:14, at least 6 contiguous amino acids selected from amino acids 204-261 of SEQ ID NO:14, at least 6 contiguous amino acids selected from amino acids 1-111 of SEQ ID NO:14, at least 8 contiguous amino acids of SEQ ID NO:16, at least 46 contiguous amino acids of SEQ ID NO:18, at least 39 contiguous amino acids selected from amino acids 13-232 of SEQ ID NO:18, at least 6 contiguous amino acids of SEQ ID NO:20, at least 7 contiguous amino acids of SEQ ID NO:22, at least 7 contiguous amino acids of SEQ ID NO:24, at least 11 contiguous amino acids of SEQ ID NO:26, at least 257 contiguous amino acids of SEQ ID NO:28, at least 6 contiguous amino acids selected from amino acids 1-31 of SEQ ID NO:28, at least 6 contiguous amino acids of SEQ ID NO:30, at least 117 contiguous amino acids of SEQ ID NO:32, at least 6 contiguous amino acids selected from amino acids 1-65 of SEQ ID NO:32, at least 6 contiguous amino acids of SEQ ID NO:34, at least 14 contiguous amino acids of SEQ ID NO:36, at least 19 contiguous amino acids of SEQ ID NO:38, at least 8 contiguous amino acids of SEQ ID NO:40, at least 7 contiguous amino acids of SEQ ID NO:42, and at least 10 contiguous amino acids of SEQ ID NO:44.

[0008] Even another embodiment of the invention is a preparation of antibodies which specifically binds to a protein comprising an amino acid sequence selected from the group consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and 44.

[0009] Still another embodiment of the invention is an isolated and purified subgenomic polynucleotide which encodes a protein comprising an amino acid sequence which is at least 85% identical to an amino acid sequence selected from the group consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and 44. Percent identity is determined using a Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 1.

[0010] A further embodiment of the invention is an isolated and purified subgenomic polynucleotide comprising a nucleotide sequence which is at least 85% identical to a nucleotide sequence selected from the group consisting of SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 31, 33, 35, 37, 39, 41, 43, 45, and the complements thereof. Percent identity is determined using a Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 1.

[0011] Another embodiment of the invention is an isolated and purified subgenomic polynucleotide which encodes an amino acid sequence selected from the group consisting of at least 95 contiguous amino acids of SEQ ID NO:2, at least 101 contiguous amino acids of SEQ ID NO:4, at least 14 contiguous amino acids selected from amino acids 1-312 of SEQ ID NO:6, at least 179 contiguous amino acids of SEQ ID NO:6, at least 75 contiguous amino acids of SEQ ID NO:6, at least 179 contiguous amino acids of SEQ ID NO:8, at least 136 contiguous amino acids of SEQ ID NO:8, at least 17 contiguous amino acids selected from amino acids 1-287 of SEQ ID NO:8, at least 82 contiguous amino acids of SEQ ID NO:10, at least 31 contiguous amino acids selected from amino acids 1-238 of SEQ ID NO:10, at least 96 contiguous amino acids of SEQ ID NO:12, at least 27 contiguous amino acids selected from amino acids 250-383 of SEQ ID NO:12, at least 6 contiguous amino acids selected from amino acids 1-184 of SEQ ID NO:12, at least 8 contiguous amino acids selected from amino acids 268-364 of SEQ ID NO:12, at least 104 contiguous amino acids of SEQ ID NO:14, at least 75 contiguous amino acids of SEQ ID NO:14, at least 17 contiguous amino acids selected from amino acids 1-150 of SEQ ID NO:14, at least 6 contiguous amino acids selected from amino acids 204-261 of SEQ ID NO:14, at least 6 contiguous amino acids selected from amino acids 1-111 of SEQ ID NO:14, at least 8 contiguous amino acids of SEQ ID NO:16, at least 46 contiguous amino acids of SEQ ID NO:18, at least 39 contiguous amino acids selected from amino acids 13-232 of SEQ ID NO:18, at least 6 contiguous amino acids of SEQ ID NO:20, at least 7 contiguous amino acids of SEQ ID NO:22, at least 7 contiguous amino acids of SEQ ID NO:24, at least 11 contiguous amino acids of SEQ ID NO:26, at least 257 contiguous amino acids of SEQ ID NO:28, at least 6 contiguous amino acids selected from amino acids 1-31 of SEQ ID NO:28, at least 6 contiguous amino acids of SEQ ID NO:30, at least 117 contiguous amino acids of SEQ ID NO:32, at least 6 contiguous amino acids selected from amino acids 1-65 of SEQ ID NO:32, at least 6 contiguous amino acids of SEQ ID NO:34, at least 14 contiguous amino acids of SEQ ID NO:36, at least 19 contiguous amino acids of SEQ ID NO:38, at least 8 contiguous amino acids of SEQ ID NO:40, at least 7 contiguous amino acids of SEQ ID NO:42, and at least 10 contiguous amino acids of SEQ ID NO:44.

[0012] Still another embodiment of the invention is an isolated and purified subgenomic-polynucleotide comprising a polynucleotide segment which hybridizes to a nucleotide sequence selected from the group consisting of SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 31, 33, 35, 37, 39, 41, and 43, and the complements thereof after washing with 0.2×SSC at 65° C., wherein the polynucleotide segment encodes a protein having an amino acid sequence selected from the group consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and 44.

[0013] Even another embodiment of the invention is an isolated and purified subgenomic polynucleotide comprising a nucleotide sequence selected from the group consisting of at least 499 contiguous nucleotides of SEQ ID NO:1, at least 1141 contiguous nucleotides of SEQ ID NO:1, at least 475 contiguous nucleotides of SEQ ID NO:3, at least 313 contiguous nucleotides selected from nucleotides 1-1001 of SEQ ID NO:3, at least 751 contiguous nucleotides of SEQ ID NO:5, at least 538 contiguous nucleotides of SEQ ID NO:5, at least 11 contiguous nucleotides selected from nucleotides 1-946 of SEQ ID NO:5, at least 13 contiguous nucleotides selected from nucleotides 1-1039 of SEQ ID NO:5, at least 651 contiguous nucleotides of SEQ ID NO:7, at least 522 contiguous nucleotides of SEQ ID NO:7, at least 11 contiguous nucleotides selected from nucleotides 1-913 of SEQ ID NO:7, at least 484 contiguous nucleotides of SEQ ID NO:9, at least 317 contiguous nucleotides of SEQ ID NO:9, at least 11 contiguous nucleotides selected from nucleotides 1-216 of SEQ ID NO:9, at least 11 contiguous nucleotides selected from nucleotides 379-812 of SEQ ID NO:9, at least 183 contiguous nucleotides selected from nucleotides 1-984 of SEQ ID NO:9, at least 594 contiguous nucleotides of SEQ ID NO:11, at least 289 contiguous nucleotides of SEQ ID NO:11, at least 11 contiguous nucleotides selected from nucleotides 1-585 of SEQ ID NO:11, at least 11 contiguous nucleotides selected from nucleotides 853-1120 of SEQ ID NO:11, at least 592 contiguous nucleotides of SEQ ID NO:13, at least 275 contiguous nucleotides of SEQ ID NO:13, at least 11 contiguous nucleotides selected from nucleotides 1-294 of SEQ ID NO:13, at least 537 contiguous nucleotides of SEQ ID NO:15, at least 294 contiguous nucleotides selected from nucleotides 1-1889 of SEQ ID NO:15, at least 171 contiguous nucleotides selected from nucleotides 318-1766 of SEQ ID NO:15, at least 11 contiguous nucleotides selected from nucleotides 1-42 of SEQ ID NO:15, at least 11 contiguous nucleotides selected from nucleotides 478-908 of SEQ ID NO:15, at least 11 contiguous nucleotides selected from nucleotides 1059-1078 of SEQ ID NO:15, at least 205 contiguous nucleotides of SEQ ID NO:17, at least 440 contiguous nucleotides of SEQ ID NO:19, at least 451 contiguous nucleotides of SEQ ID NO:21, at least 11 contiguous nucleotides selected from nucleotides 1-121 of SEQ ID NO:21, at least 11 contiguous nucleotides selected from nucleotides 474-592 of SEQ ID NO:21, at least 351 contiguous nucleotides of SEQ ID NO:23, at least 21 contiguous nucleotides selected from nucleotides 1-1943 of SEQ ID NO:23, at least 11 contiguous nucleotides selected from 1-612 of SEQ ID NO:23, at least 11 contiguous nucleotides selected from nucleotides 611-719 of SEQ ID NO:23, at least 11 contiguous nucleotides selected from nucleotides 713-830 of SEQ ID NO:23, at least 11 contiguous nucleotides selected from nucleotides 830-1933 of SEQ ID NO:23, at least 492 nucleotides of SEQ ID NO:25, at least 11 contiguous nucleotides selected from nucleotides 758-847 of SEQ ID NO:25, at least 1024 contiguous nucleotides of SEQ ID NO:27, at least 347 contiguous nucleotides of SEQ ID NO:29, at least 11 contiguous nucleotides selected from nucleotides 548-601 of SEQ ID NO:29, at least 394 contiguous nucleotides of SEQ ID NO:31, at least 11 contiguous nucleotides selected from nucleotides 1-361 of SEQ ID NO:31, at least 11 contiguous nucleotides selected from nucleotides 1083-1102 of SEQ ID NO:31, at least 492 contiguous nucleotides of SEQ ID NO:33, at least 510 contiguous nucleotides of SEQ ID NO:35, at least 11 contiguous nucleotides selected from nucleotides 1-502 or 505-631 of SEQ ID NO:35, at least 392 contiguous nucleotides of SEQ ID NO:37, at least 11 contiguous nucleotides selected from nucleotides 1-502 of SEQ ID NO:37, at least 11 contiguous nucleotides selected from nucleotides 505-631 of SEQ ID NO:37, at least 559 contiguous nucleotides of SEQ ID NO:39, at least 11 contiguous nucleotides selected from nucleotides 1-92 of SEQ ID NO:39, at least 254 contiguous nucleotides of SEQ ID NO:41, at least 11 contiguous nucleotides selected from nucleotides 1-34 of SEQ ID NO:41 at least 11 contiguous nucleotides selected from nucleotides 55-110 of SEQ ID NO:41, at least 103 contiguous nucleotides of SEQ ID NO:43, at least 11 contiguous nucleotides selected from nucleotides 1-280 of SEQ ID NO:43, at least 11 contiguous nucleotides selected from nucleotides 270-319 of SEQ ID NO:43, at least 11 contiguous nucleotides selected from nucleotides 378-423 of SEQ ID NO:43, at least 11 contiguous nucleotides selected from nucleotides 414-492 of SEQ ID NO:43, at least 11 contiguous nucleotides selected from nucleotides 532-570 of SEQ ID NO:43, at least 11 contiguous nucleotides selected from nucleotides 1086-1152 of SEQ ID NO:43, and the complements thereof.

[0014] A further embodiment of the invention is a construct comprising isolated and purified subgenomic polynucleotides of the invention.

[0015] Another embodiment of the invention is a host cell comprising a construct of the invention.

[0016] Yet another embodiment of the invention is a process for producing a protein. A culture of a host cell comprising a construct of the invention is grown in a suitable culture medium. The protein secreted from the host cell is purified.

[0017] Another embodiment of the invention is a polynucleotide array comprising at least one single-stranded polynucleotide which comprises at least 12 contiguous nucleotides of a nucleotide sequence selected from the group consisting of SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, and the complements thereof.

[0018] Even another embodiment of the invention is a method of detecting differential gene expression between two biological samples. A first biological sample comprising single-stranded polynucleotide molecules with a first polynucleotide array comprising at least one single-stranded polynucleotide which comprises at least 12 contiguous nucleotides of a nucleotide sequence selected from the group consisting of SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, and the complements thereof. A second biological sample comprising single-stranded polynucleotide molecules is contacted with a second polynucleotide array. The first and second polynucleotide arrays comprise identical single-stranded polynucleotides. A first and second pattern of double-stranded polynucleotides bound to the first and second polynucleotide arrays are detected. A difference between the first and second patterns indicates a gene which is differentially expressed between the first and second biological samples.

[0019] Methods are also provided for preventing, treating, or ameliorating a medical condition associated with hematopoiesis or bone marrow morphogenesis, which comprises administering to a mammalian subject a therapeutically effective amount of a composition comprising a protein of the present invention and a pharmaceutically acceptable carrier.

[0020] Proteins encoded by polynucleotides of the present invention have potential uses in stimulating blood cell generation in patient receiving cancer chemotherapy, for bone marrow transplantation patient, and for healing fractured bones.

DETAILED DESCRIPTION OF THE INVENTION

[0021] Secreted proteins include proteins which, when expressed in a suitable host cell, are transported across or through a membrane, including transport as a result of signal sequences. Secreted proteins include proteins which are secreted wholly (e.g., soluble proteins) or partially (e.g., receptors) from the cell in which they are expressed. Secreted proteins also include proteins which are transported across the membrane of the endoplasmic reticulum.

[0022] Polynucleotides of the invention which encode secreted proteins were isolated from a cDNA library derived from human bone marrow stromal cells. Subgenomic polynucleotides of the invention contain less than a whole chromosome and can be single- or double-stranded. Preferably, the polynucleotides are intron-free. Subgenomic polynucleotides of the invention can comprise all or a portion of a nucleotide sequence disclosed in SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, or 43, as explained in detail below. The complements of these nucleotide sequences are contiguous nucleotide sequences which form Watson-Crick base pairs with a contiguous nucleotide sequence as shown in SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, or 43. These complementary sequences are also subgenomic polynucleotides and can be used, inter alia, to provide antisense oligonucleotides.

[0023] Degenerate nucleotide sequences encoding amino acid sequences of proteins of the invention, as well as homologous nucleotide sequences which are at least 65%, 75%, 85%, 90%, 95%, 98%, or 99% identical to the nucleotide sequences shown in NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, and 43, are also subgenomic polynucleotides of the invention. Percent identity is determined using computer programs which employ the Smith-Waterman homology search algorithm, for example as implemented in the MPSRCH program (Oxford Molecular), using an affine gap search with the following parameters: a gap open penalty of 12 and a gap extension penalty of 1. The Smith-Waterman algorithm is taught in Smith and Waterman, Adv. Appl. Math. (1981) 2:482-489.

[0024] Typically, homologous sequences can be confirmed by hybridization under stringent conditions, as is known in the art. For example, using the following wash conditions-2×SSC (0.3 M NaCl, 0.03 M sodium citrate, pH 7.0), 0.1% SDS, room temperature twice, 30 minutes each; then 2×SSC, 0.1% SDS, 50° C. once, 30 minutes; then 2×SSC, room temperature twice, 10 minutes each-homologous sequences can be identified which contain at most about 25-30% basepair mismatches. More preferably, homologous nucleic acid strands contain 15-25% basepair mismatches, even more preferably 5-15% basepair mismatches.

[0025] Species homologs of subgenomic polynucleotides of the invention can also be identified by making suitable probes or primers and screening cDNA expression libraries from other species, such as mice, monkeys, yeast, or bacteria, as well as human cDNA expression libraries. It is well known that the T_(m) of a double-stranded DNA decreases by 1-1.5° C. with every 1% decrease in homology (Bonner et al., J. Mol. Biol. 81, 123 (1973). Homologous subgenomic polynucleotide species can therefore be identified, for example, by hybridizing a putative homologous polynucleotide with a polynucleotide having a nucleotide sequence disclosed in SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, or 43to form a test hybrid, comparing the melting temperature of the test hybrid with the melting temperature of a hybrid comprising a polynucleotide having one of the disclosed nucleotide sequences and a polynucleotide which is perfectly complementary to that sequence, and calculating the number or percent of basepair mismatches within the test hybrid.

[0026] Nucleotide sequences which hybridize to the coding sequences shown in SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, or 43 or their complements following stringent hybridization and/or wash conditions are also subgenomic polynucleotides of the invention. Stringent wash conditions are well known and understood in the art and are disclosed, for example, in Sambrook et al., MOLECULAR CLONING: A LABORATORY MANUAL, 2d ed., 1989, at pages 9.50-9.51.

[0027] Typically, for stringent hybridization conditions a combination of temperature and salt concentration should be chosen that is approximately 12-20° C. below the calculated T_(m) of the hybrid under study. The T_(m) of a hybrid between a nucleotide sequence shown in SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, or 43 and a polynucleotide sequence which is 65%, 75%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to that sequence can be calculated, for example, using the equation of Bolton and McCarthy, Proc. Natl. Acad. Sci. U.S.A. 48, 1390 (1962):

T _(m)=81.5° C.−16.6(log₁₀[Na⁺])+0.41(%G+C)−0.63(%formamide)−600/l), where l=the length of the hybrid in basepairs.

[0028] Stringent wash conditions include, for example, 4×SSC at 65° C., or 50% formamide, 4×SSC at 42° C., or 0.5×SSC, 0.1% SDS at 65° C. Highly stringent wash conditions include, for example, 0.2×SSC at 65° C.

[0029] Subgenomic polynucleotides can be isolated and purified free from other nucleotide sequences using standard nucleic acid purification techniques. For example, restriction enzymes and probes can be used to isolate polynucleotide fragments which comprise nucleotide sequences of the invention. Isolated and purified subgenomic polynucleotides are in preparations which are free or at least 90% free of other molecules.

[0030] Complementary DNA (cDNA) molecules with coding sequences corresponding to SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17,19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, or 43 are also subgenomic polynucleotides of the invention. cDNA molecules of the invention can be made with standard molecular biology techniques, using human mRNA as a template. cDNA molecules can thereafter be replicated using molecular biology techniques known in the art and disclosed in manuals such as Sambrook et al., 1989. An amplification technique, such as the polymerase chain reaction (PCR), can be used to obtain additional copies of subgenomic polynucleotides of the invention, using either human genomic DNA or CDNA as a template.

[0031] Alternatively, synthetic chemistry techniques can be used to synthesize subgenomic polynucleotide molecules of the invention. The degeneracy of the genetic code allows alternate nucleotide sequences to be synthesized which will encode a protein having an amino acid sequence shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, or 44 or a biologically active variant of one of those sequences. All such nucleotide sequences are within the scope of the present invention.

[0032] The invention also provides polynucleotide probes which can be used, for example, in hybridization protocols such as Northern or Southern blotting or in situ hybridizations. Polynucleotide probes of the invention comprise at least 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, or 40 or more contiguous nucleotides selected from SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, or 43. Polynucleotide probes of the invention can comprise a detectable label, such as a radioisotopic, fluorescent, enzymatic, or chemiluminescent label.

[0033] Subgenomic polynucleotides of the invention can be used as primers to obtain additional copies of the polynucleotides. Subgenomic polynucleotides of the invention can also be used to express mRNA, protein, polypeptides, antibodies, or fusion proteins of the invention and to generate antisense oligonucleotides and ribozymes.

[0034] Isolated polynucleotides of the invention can be present in constructs, such as DNA or RNA constructs. They can be operably linked to a promoter or other expression control sequence in order to produce proteins of the invention recombinantly. Many suitable expression control sequences, such as the pMT2 or pED expression vectors disclosed in Kaufman et al., Nucleic Acids Res. 19, 4485-4490 (1991), are well known in the art. General methods of expressing recombinant proteins are also well known (see, e.g., Kaufman, METHODS IN ENZYMOLOGY 185, 537-566, 1990). An isolated polynucleotide and a promoter or an expression control sequence are operably linked when the isolated polynucleotide and the promoter or expression control sequence are situated within a construct or cell in such a way that the protein is expressed by a host cell which has been transformed or transfected with the polynucleotide and the promoter or expression control sequence.

[0035] For example, a construct of the invention can comprise a promoter which is functional in a particular type of host cell. The skilled artisan can readily select an appropriate promoter from the large number of cell type-specific promoters known and used in the art. The polynucleotide is located downstream from the promoter. Constructs of the invention can also contain a transcription terminator which is functional in the host cell. Transcription of the polynucleotide segment initiates at the promoter. A construct can be linear or circular and can contain sequences, if desired, for autonomous replication.

[0036] A variety of host cells are available for use in bacterial, yeast, insect, and human expression systems and can be used to propagate or to express polynucleotides of the invention. Constructs comprising the polynucleotides can be introduced into host cells using any technique known in the art. These techniques include transferrin-polycation-mediated DNA transfer, transfection with naked or encapsulated nucleic acids, liposome-mediated cellular fusion, intracellular transportation of DNA-coated latex beads, protoplast fusion, viral infection, electroporation, and calcium phosphate-mediated transfection.

[0037] Polynucleotides of the invention can be propagated in constructs and cell lines using techniques well known in the art. Polynucleotides can be on linear or circular molecules. They can be on autonomously replicating molecules or on molecules without replication sequences. They can be regulated by their own or by other regulatory sequences, as are known in the art.

[0038] Bacterial systems for expressing polynucleotides of the invention include those described in Chang et al., Nature (1978) 275: 615, Goeddel et al., Nature (1979) 281: 544, Goeddel et al., Nucleic Acids Res. (1980) 8: 4057, EP 36,776, U.S. Pat. No. 4,551,433, deBoer et al., Proc. Natl. Acad. Sci. USA (1983) 80: 21-25, and Siebenlist et al., Cell (1980) 20: 269.

[0039] Expression systems in yeast include those described in Hinnen et al., Proc. Natl. Acad. Sci. USA (1978) 75: 1929;Ito et al., J. Bacteriol. (1983) 153: 163; Kurtz et al., Mol. Cell. Biol. (1986) 6: 142; Kunze et al., J. Basic Microbiol. (1985) 25: 141; Gleeson et al., J. Gen. Microbiol. (1986) 132: 3459, Roggenkamp et al., Mol. Gen. Genet. (1986) 202:302) Das et al., J. Bacteriol. (1984) 158: 1165; De Louvencourt et al., J. Bacteriol (1983) 154: 737, Van den Berg et al., Bio/Technology (1990) 8: 135; Kunze et al, J. Basic Microbiol. (1985) 25: 141; Cregg et al., Mol. Cell. Biol. (1985) 5: 3376, U.S. Pat. Nos. 4,837,148, 4,929,555; Beach and Nurse, Nature (1981) 300: 706; Davidow et al., Curr. Genet. (1985) 10: 380, Gaillardin et al., Curr. Genet. (1985) 10: 49, Ballance et al., Biochem. Biophys. Res. Commun. (1983) 112: 284-289; Tilburn et al., Gene (1983) 26: 205-221, Yelton et al., Proc. Natl. Acad. Sci. USA (1984) 81: 1470-1474, Kelly and Hynes, EMBO J. (1985) 4: 475479; EP 244,234, and WO 91/00357.

[0040] Expression of polynucleotides of the invention in insects can be carried out as described in U.S. Pat. No. 4,745,051, Friesen et al. (1986) “The Regulation of Baculovirus Gene Expression” in: THE MOLECULAR BIOLOGY OF BACULOVIRUSES (W. Doerfler, ed.), EP 127,839, EP 155,476, and Vlak et al., J. Gen. Virol. (1988) 69: 765-776, Miller et al., Ann. Rev. Microbiol. (1988) 42: 177, Carbonell et al., Gene (1988) 73: 409, Maeda et al., Nature (1985) 315: 592-594, Lebacq-Verheyden et al., Mol. Cell. Biol. (1988) 8: 3129; Smith et al., Proc. Natl. Acad. Sci USA (1985) 82: 8404, Miyajima et al., Gene (1987) 58: 273; and Martin et al., DNA (1988) 7:99. Numerous baculoviral strains and variants and corresponding permissive insect host cells from hosts are described in Luckow et al., Bio/Technology (1988) 6: 47-55, Miller et al., in GENETIC ENGINEERING (Setlow, J. K. et al. eds.), Vol. 8 (Plenum Publishing, 1986), pp. 277-279, and Maeda et al., Nature, (1985) 315: 592-594.

[0041] Mammalian expression of polynucleotides can be achieved as described in Dijkema et al., EMBO J. (1985) 4: 761, Gorman et al., Proc. Natl. Acad. Sc. USA (1982b) 79: 6777, Boshart et al., Cell (1985) 41: 521 and U.S. Pat. No. 4,399,216. Other features of mammalian expression can be facilitated as described in Ham and Wallace, Meth. Enz. (1979) 58: 44, Barnes and Sato, Anal. Biochem. (1980) 102: 255, U.S. Pat. Nos. 4,767,704, 4,657,866, 4,927,762, 4,560,655, WO 90/103430, WO 87/00195, and U.S. RE 30,985.

[0042] Polynucleotides of the invention can also be used in gene delivery vehicles, for the purpose of delivering an mRNA or oligonucleotide (either with the sequence of a native mRNA or its complement), full-length protein, fusion protein, polypeptide, or ribozyme, or single-chain antibody, into a cell, preferably a eukaryotic cell. According to the present invention, a gene delivery vehicle can be, for example, naked plasmid DNA, a viral expression vector comprising a polynucleotide of the invention, or a polynucleotide of the invention in conjunction with a liposome or a condensing agent.

[0043] In one embodiment of the invention, the gene delivery vehicle comprises a promoter and one of the polynucleotides disclosed herein. Preferred promoters are tissue-specific promoters and promoters which are activated by cellular proliferation, such as the thymidine kinase and thymidylate synthase promoters. Other preferred promoters include promoters which are activatable by infection with a virus, such as the α- and β-interferon promoters, and promoters which are activatable by a hormone, such as estrogen. Other promoters which can be used include the Moloney virus LTR, the CMV promoter, and the mouse albumin promoter.

[0044] A gene delivery vehicle can comprise viral sequences such as a viral origin of replication or packaging signal. These viral sequences can be selected from viruses such as astrovirus, coronavirus, orthomyxovirus, papovavirus, paramyxovirus, parvovirus, picomavirus, poxvirus, retrovirus, togavirus or adenovirus. In a preferred embodiment, the gene delivery vehicle is a recombinant retroviral vector. Recombinant retroviruses and various uses thereof have been described in numerous references including, for example, Mann et al., Cell 33:153, 1983, Cane and Mulligan, Proc. Nat'l. Acad. Sci. USA 81:6349, 1984, Miller et al., Human Gene Therapy 1:5-14, 1990, U.S. Pat. Nos. 4,405,712, 4,861,719, and 4,980,289, and PCT Application Nos. WO 89/02,468, WO 89/05,349, and WO 90/02,806. Numerous retroviral gene delivery vehicles can be utilized in the present invention, including for example those described in EP 0,415,731; WO 90/07936; WO 94/03622; WO 93/25698; WO 93/25234; U.S. Pat. No. 5,219,740; WO 9311230; WO 9310218; Vile and Hart, Cancer Res. 53:3860-3864, 1993; Vile and Hart, Cancer Res. 53:962-967, 1993; Ram et al, Cancer Res. 53:83-88, 1993; Takamiya et al., J. Neurosci. Res. 33:493-503, 1992; Baba et al., J. Neurosurg. 79:729-735, 1993 (U.S. Pat. No. 4,777,127, GB 2,200,651, EP 0,345,242 and WO 91/02805).

[0045] Particularly preferred retroviruses are derived from retroviruses which include avian leukosis virus (ATCC Nos. VR-535 and VR-247), bovine leukemia virus (VR-1315), murine leukemia virus (MLV), mink-cell focus -inducing virus (Koch et al., J. Vir. 49:828, 1984; and Oliffet al., J. Vir. 48:542, 1983), murine sarcoma virus (ATCC Nos. VR-844, 45010 and 45016), reticuloendotheliosis virus (ATCC Nos. VR-994, VR-770 and 45011), Rous sarcoma virus, Mason-Pfizer monkey virus, baboon endogenous virus, endogenous feline retrovirus (e.g., RD114), and mouse or rat gL30 sequences used as a retroviral vector. Particularly preferred strains of MLV from which recombinant retroviruses can be generated include 4070A and 1504A (Hartley and Rowe, J. Vir. 19:19, 1976), Abelson (ATCC No. VR-999), Friend (ATCC No. VR-245), Graffi (Ru et al., J. Vir. 67:4722, 1993; and Yantchev Neoplasma 26:397, 1979), Gross (ATCC No. VR-590), Kirsten (Albino et al., J. Exp. Med. 164:1710, 1986), Harvey sarcoma virus (Manly et al., J. Vir. 62:3540, 1988; and Albino et al., J. Exp. Med. 164:1710, 1986) and Rauscher (ATCC No. VR-998), and Moloney MLV (ATCC No. VR-190). A particularly preferred non-mouse retrovirus is Rous sarcoma virus. Preferred Rous sarcoma viruses include Bratislava (Manly et al., J. Vir. 62:3540, 1988; and Albino et al.,J. Exp. Med. 164:1710, 1986), Bryan high titer (e.g., ATCC Nos. VR-334, VR-657, VR-726, VR-659, and VR-728), Bryan standard (ATCC No. VR-140), Carr-Zilber (Adgighitov et al., Neoplasma 27:159, 1980), Engelbreth-Holm (Laurent et al., Biochem Biophys Acta 908:241, 1987), Harris, Prague (e.g, ATCC Nos. VR-772, and 45033), and Schmidt-Ruppin (e.g. ATCC Nos. VR-724, VR-725, VR-354) viruses.

[0046] Any of the above retroviruses can be readily utilized in order to assemble or construct retroviral gene delivery vehicles given the disclosure provided herein and standard recombinant techniques (e.g., Sambrook et al., 1989, and Kunkle, Proc. Natl. Acad. Sci. U.S.A. 82:488, 1985) known in the art. Portions of retroviral expression vectors can be derived from different retroviruses. For example, retrovector LTRs can be derived from a murine sarcoma virus, a tRNA binding site from a Rous sarcoma virus, a packaging signal from a murine leukemia virus, and an origin of second strand synthesis from an avian leukosis virus. These recombinant retroviral vectors can be used to generate transduction competent retroviral vector particles by introducing them into appropriate packaging cell lines (see Ser. No. 07/800,921, filed Nov. 29, 1991). Recombinant retroviruses can be produced which direct the site-specific integration of the recombinant retroviral genome into specific regions of the host cell DNA. Such site-specific integration can be mediated by a chimeric integrase incorporated into the retroviral particle (see Ser. No.08/445,466 filed May 22, 1995). It is preferable that the recombinant viral gene delivery vehicle is a replication-defective recombinant virus.

[0047] Packaging cell lines suitable for use with the above-described retroviral gene delivery vehicles can be readily prepared (see Ser. No.08/240,030, filed May 9, 1994; see also WO 92/05266) and used to create producer cell lines (also termed vector cell lines or “VCLs”) for production of recombinant viral particles. In particularly preferred embodiments of the present invention, packaging cell lines are made from human (e.g., HT1080 cells) or mink parent cell lines, thereby allowing production of recombinant retroviral gene delivery vehicles which are capable of surviving inactivation in human serum. The construction of recombinant retroviral gene delivery vehicles is described in detail in WO 91/02805. These recombinant retroviral gene delivery vehicles can be used to generate transduction competent retroviral particles by introducing them into appropriate packaging cell lines (see Ser. No. 07/800,921). Similarly, adenovirus gene delivery vehicles can also be readily prepared and utilized given the disclosure provided herein (see also Berkner, Biotechniques 6:616-627,1988, and Rosenfeld et al., Science 252:431-434, 1991, WO 93/07283, WO 93/06223, and WO 93/07282).

[0048] A gene delivery vehicle can also be a recombinant adenoviral gene delivery vehicle. Such vehicles can be readily prepared and utilized given the disclosure provided herein (see Berkner, Biotechniques 6:616, 1988, and Rosenfeld et al., Science 252:431, 1991, WO 93/07283, WO 93/06223, and WO 93/07282). Adeno-associated viral gene delivery vehicles can also be constructed and used to deliver proteins or polynucleotides of the invention to cells in vitro or in vivo. The use of adeno-associated viral gene delivery vehicles in vitro is described in Chattedjee et al., Science 258:1485-1488 (1992), Walsh et al., Proc. Nat'l. Acad. Sci. 89: 7257-7261 (1992), Walsh et al., J. Clin. Invest. 94: 1440-1448 (1994), Flotte et al., J. Biol. Chem. 268: 3781-3790 (1993), Ponnazhagan et al., J. Exp. Med 179: 733-738 (1994), Miller et al., Proc. Nat'l Acad. Sci. 91: 10183-10187 (1994), Einerhand et al., Gene Ther. 2: 336-343 (1995), Luo et al., Exp. Hematol. 23: 1261-1267 (1995), and Zhou et al., Gene Therapy 3: 223-229 (1996). In vivo use of these vehicles is described in Flotte et al., Proc. Nat'l Acad. Sci. 90: 10613-10617 (1993), and Kaplitt et al., Nature Genet. 8:148-153 (1994).

[0049] In another embodiment of the invention, a gene delivery vehicle is derived from a togavirus. Preferred togaviruses include alphaviruses, in particular those described in U.S. Ser. No. 08/405,627, filed Mar. 15, 1995, WO 95/07994. Alpha viruses, including Sindbis and ELVS viruses can be gene delivery vehicles for polynucleotides of the invention. Alpha viruses are described in WO 94/21792, WO 92/10578 and WO 95/07994. Several different alphavirus gene delivery vehicle systems can be constructed and used to deliver polynucleotides to a cell according to the present invention. Representative examples of such systems include those described in U.S. Pat. Nos. 5,091,309 and 5,217,879. Particularly preferred alphavirus gene delivery vehicles for use in the present invention include those which are described in WO 95/07994, and U.S. Ser. No. 08/405,627.

[0050] Preferably, the recombinant viral vehicle is a recombinant alphavirus viral vehicle based on a Sindbis virus. Sindbis constructs, as well as numerous similar constructs, can be readily prepared essentially as described in U.S. Ser. No. 08/198,450. Sindbis viral gene delivery vehicles typically comprise a 5′ sequence capable of initiating Sindbis virus transcription, a nucleotide sequence encoding Sindbis non-structural proteins, a viral junction region inactivated so as to prevent fragment transcription, and a Sindbis RNA polymerase recognition sequence. Optionally, the viral junction region can be modified so that polynucleotide transcription is reduced, increased, or maintained. As will be appreciated by those in the art, corresponding regions from other alphaviruses can be used in place of those described above.

[0051] The viral junction region of an alphavirus-derived gene delivery vehicle can comprise a first viral junction region which has been inactivated in order to prevent transcription of the polynucleotide and a second viral junction region which has been modified such that polynucleotide transcription is reduced. An alphavirus-derived vehicle can also include a 5′ promoter capable of initiating synthesis of viral RNA from cDNA and a 3′ sequence which controls transcription termination.

[0052] Other recombinant togaviral gene delivery vehicles which can be utilized in the present invention include those derived from Semliki Forest virus (ATCC VR-67; ATCC VR-1247), Middleberg virus (ATCC VR-370), Ross River virus (ATCC VR-373 ATCC VR-1246), Venezuelan equine encephalitis virus (ATCC VR923; ATCC VR-1250; ATCC VR-1249; ATCC VR-532), and those described in U.S. Pat. Nos. 5,091,309 and 5,217,879 and in WO 92/10578. The Sindbis vehicles described above, as well as numerous similar constructs, can be readily prepared essentially as described in U.S. Ser. No. 08/198,450.

[0053] Other viral gene delivery vehicles suitable for use in the present invention include, for example, those derived from poliovirus (Evans et al., Nature 339:385, 1989, and Sabin et al., J. Biol. Standardization 1:115, 1973) (ATCC VR-58); rhinovirus (Arnold et al., J. Cell Biochem. L401, 1990) (ATCC VR-1110); pox viruses, such as canary pox virus or vaccinia virus (Fisher-Hoch et al., PROC. NATL. ACAD. SCI. U.S.A. 86:317, 1989; Flexner et al., Ann. N.Y. Acad. Sci. 569:86, 1989; Flexner et al., Vaccine 8:17,1990; U.S. Pat. Nos. 4,603,112 and 4,769,330; WO 89/01973) (ATCC VR-111; ATCC VR-2010); SV40 (Mulligan et al., Nature 277:108,1979) (ATCC VR-305), (Madzak et al., J. Gen. Vir. 73:1533, 1992); influenza virus (Luytjes et al., Cell 59:1107, 1989; McMicheal et al., The New England Journal of Medicine 309:13, 1983; and Yap et al., Nature 273:238, 1978) (ATCC VR-797); parvovirus such as adeno-associated virus (Samulski et al., J. Vir. 63:3822, 1989, and Mendelson et al., Virology 166:154, 1988) (ATCC VR-645); herpes simplex virus (Kit et al., Adv. Exp. Med. Biol. 215:219, 1989) (ATCC VR-977; ATCC VR-260); Nature 277:108, 1979); human immunodeficiency virus (EPO 386,882, Buchschacher et al., J. Vir. 66:2731, 1992); measles virus (EPO 440,219) (ATCC VR-24); A (ATCC VR-67; ATCC VR-1247), Aura (ATCC VR-368), Bebaru virus (ATCC VR-600; ATCC VR-1240), Cabassou (ATCC VR-922), Chikungunya virus (ATCC VR-64; ATCC VR-1241), Fort Morgan (ATCC VR-924), Getah virus (ATCC VR-369; ATCC VR-1243), Kyzylagach (ATCC VR-927), Mayaro (ATCC VR-66), Mucambo virus (ATCC VR-580; ATCC VR-1244), Ndumu (ATCC VR-371), Pixuna virus (ATCC VR-372; ATCC VR-1245), Tonate (ATCC VR-925), Triniti (ATCC VR-469), Una (ATCC VR-374), Whataroa (ATCC VR-926), Y-62-33 (ATCC VR-375), O'Nyong virus, Eastern encephalitis virus (ATCC VR-65; ATCC VR-1242), Western encephalitis virus (ATCC VR-70; ATCC VR-1251; ATCC VR-622; ATCC VR-1252), and coronavirus (Hamre et al., Proc. Soc. Exp. Biol. Med. 121:190, 1966) (ATCC VR-740).

[0054] A polynucleotide of the invention can also be combined with a condensing agent to form a gene delivery vehicle. In a preferred embodiment, the condensing agent is a polycation, such as polylysine, polyarginine, polyornithine, protamine, spermine, spermidine, and putrescine. Many suitable methods for making such linkages are known in the art (see, for example, Ser. No. 08/366,787, filed Dec. 30, 1994).

[0055] In an alternative embodiment, a polynucleotide is associated with a liposome to form a gene delivery vehicle. Liposomes are small, lipid vesicles comprised of an aqueous compartment enclosed by a lipid bilayer, typically spherical or slightly elongated structures several hundred Angstroms in diameter. Under appropriate conditions, a liposome can fuse with the plasma membrane of a cell or with the membrane of an endocytic vesicle within a cell which has internalized the liposome, thereby releasing its contents into the cytoplasm. Prior to interaction with the surface of a cell, however, the liposome membrane acts as a relatively impermeable barrier which sequesters and protects its contents, for example, from degradative enzymes. Additionally, because a liposome is a synthetic structure, specially designed liposomes can be produced which incorporate desirable features. See Stryer, Biochemistry, pp. 236-240, 1975 (W. H. Freeman, San Francisco, Calif.); Szoka et al., Biochim. Biophys. Acta 600:1, 1980; Bayer et al., Biochim. Biophys. Acta. 550:464, 1979; Rivnay et al., Meth. Enzymol. 149:119, 1987; Wang et al., PROC. NATL. ACAD. SCI. U.S.A. 84: 7851, 1987, Plant et al., Anal. Biochem. 176:420, 1989, and U.S. Pat. No. 4,762,915. Liposomes can encapsulate a variety of nucleic acid molecules including DNA, RNA, plasmids, and expression constructs comprising polynucleotides such those disclosed in the present invention.

[0056] Liposomal preparations for use in the present invention include cationic (positively charged), anionic (negatively charged) and neutral preparations. Cationic liposomes have been shown to mediate intracellular delivery of plasmid DNA (Felgner et al., Proc. Natl. Acad. Sci. USA 84:7413-7416, 1987), mRNA (Malone et al., Proc. Natl. Acad. Sci. USA 86:6077-6081, 1989), and purified transcription factors (Debs et al., J. Biol. Chem. 265:10189-10192, 1990), in functional form. Cationic liposomes are readily available. For example, N[1-2,3-dioleyloxy)propyl]-N,N,N-triethylammonium (DOTMA) liposomes are available under the trademark Lipofectin, from GIBCO BRL, Grand Island, N.Y. See also Felgner et al., Proc. Natl. Acad. Sci. USA 91: 5148-5152.87, 1994. Other commercially available liposomes include Transfectace (DDAB/DOPE) and DOTAP/DOPE (Boerhinger). Other cationic liposomes can be prepared from readily available materials using techniques well known in the art. See, e.g., Szoka et al., Proc. Natl. Acad. Sci. USA 75:4194-4198, 1978; and WO 90/11092 for descriptions of the synthesis of DOTAP (1,2-bis(oleoyloxy)-3-(trimethylammonio)propane) liposomes.

[0057] Similarly, anionic and neutral liposomes are readily available, such as from Avanti Polar Lipids (Birmingham, Ala.), or can be easily prepared using readily available materials. Such materials include phosphatidyl choline, cholesterol, phosphatidyl ethanolamine, dioleoylphosphatidyl choline (DOPC), dioleoylphosphatidyl glycerol (DOPG), dioleoylphoshatidyl ethanolamine (DOPE), among others. These materials can also be mixed with the DOTMA and DOTAP starting materials in appropriate ratios. Methods for making liposomes using these materials are well known in the art.

[0058] The liposomes can comprise multilammelar vesicles (MLVs), small unilamellar vesicles (SUVs), or large unilamellar vesicles (LUVs). The various liposome-nucleic acid complexes are prepared using methods known in the art. See, e.g., Straubinger et al., METHODS OF IMMUNOLOGY (1983), Vol. 101, pp. 512-527; Szoka et al., Proc. Natl. Acad. Sci. USA 87:3410-3414, 1990; Papahadjopoulos et al., Biochim. Biophys. Acta 394:483, 1975; Wilson et al., Cell 17:77, 1979; Deamer and Bangham, Biochim. Biophys. Acta 443:629, 1976; Ostro et al., Biochem. Biophys. Res. Commun. 76:836, 1977; Fraley et al., Proc. Natl. Acad. Sci. USA 76:3348, 1979; Enoch and Strittmatter, Proc. Natl. Acad. Sci. USA 76:145, 1979; Fraley et al., J. Biol. Chem. 255:10431, 1980; Szoka and Papahadjopoulos, Proc. Natl. Acad. Sci. USA 75:145, 1979; and Schaefer-Ridder et al., Science 215:166, 1982.

[0059] In addition, lipoproteins can be included with a polynucleotide of the invention for delivery to a cell. Examples of such lipoproteins include chylomicrons, HDL, IDL, LDL, and VLDL. Mutants, fragments, or fusions of these proteins can also be used. Modifications of naturally occurring lipoproteins can also be used, such as acetylated LDL. These lipoproteins can target the delivery of polynucleotides to cells expressing lipoprotein receptors. Preferably, if lipoproteins are included with a polynucleotide, no other targeting ligand is included in the composition.

[0060] In another embodiment, naked polynucleotide molecules are used as gene delivery vehicles, as described in WO 90/11092 and U.S. Pat. No.5,580,859. Such gene delivery vehicles can be either DNA or RNA and, in certain embodiments, are linked to killed adenovirus. Curiel et al., Hum. Gene. Ther. 3:147-154, 1992. Other suitable vehicles include DNA-ligand (Wu et al., J. Biol. Chem. 264:16985-16987, 1989), lipid-DNA combinations (Felgner et al., Proc. Natl. Acad. Sci. USA 84:7413 7417, 1989), liposomes (Wang et al., Proc. Natl. Acad. Sci. 84:7851-7855, 1987) and microprojectiles (Williams et al., Proc. Natl. Acad. Sci. 88:2726-2730, 1991).

[0061] One can increase the efficiency of naked polynucleotide uptake into cells by coating the polynucleotides onto biodegradable latex beads. This approach takes advantage of the observation that latex beads, when incubated with cells in culture, are efficiently transported and concentrated in the perinuclear region of the cells. The beads will then be transported into cells when injected into muscle. Polynucleotide-coated latex beads will be efficiently transported into cells after endocytosis is initiated by the latex beads and thus increase gene transfer and expression efficiency. This method can be improved further by treating the beads to increase their hydrophobicity, thereby facilitating the disruption of the endosome and release of polynucleotides into the cytoplasm.

[0062] One polynucleotide of the invention is designated hCornichon. The nucleotide sequence of hCornichon is shown in SEQ ID NO:1. hCornichon cDNA represents a transcript of 1325 nucleotides with a translation stop codon (TAG) at position 428, a polyadenylation signal (AATAAA) (SEQ ID NO:45) at position 1292, and a poly(A) tail at position 1316. The DNA sequence between nucleotides 2 and 427 encodes a protein of 142 amino acids, as shown in SEQ ID NO:2. A potential signal peptide is located in the first 28 amino acid residues. An hCornichon polynucleotide can comprise at least 499, 550, 600, 700, 750, 800, 850, 850, 900, 950, 1000, 1100, 1141, 1150, 1200, or 1250 nucleotides of SEQ ID NO:1 or the complements thereof.

[0063] Another polynucleotide of the invention is designated BMS46. The nucleotide sequence of BMS46 is shown in SEQ ID NO:3. BMS46 cDNA represents a transcript of 1277 nucleotides with a translation start codon (ATG) at position 656, a translation stop codon (TAG) at position 1223, a polyadenylation signal (AATAAA) (SEQ ID NO:45) at position 1243, and a poly(A) tail at position 1260. The DNA sequence between nucleotides 656 and 1222 encodes a protein of 189 amino acid residues, as shown in SEQ ID NO:4. A potential signal peptide is located in the first 47 amino acid residues. A BMS46 polynucleotide can comprise at least 474, 475, 476, 477, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1150, 1200, or 1250 contiguous nucleotides of SEQ ID NO:3, or at least 313, 314, 315, or 316 contiguous nucleotides selected from nucleotides 1-1001 of SEQ ID NO:3, or the complements thereof.

[0064] The nucleotide sequence of another polynucleotide of the invention, termed BMS112, is shown in SEQ ID NO:5. BMS112 cDNA represents a transcript of 1610 nucleotides with a translation start codon (ATG) at position 132, a translation stop codon (TGA) at position 1251, a polyadenylation signal (AATAAA) (SEQ ID NO:45) at position 1516, and a poly(A) tail at position 1594. The DNA sequence between nucleotides 132 and 1250 encodes a polypeptide of 373 amino acid residues (SEQ ID NO:6). A BMSI 112 polynucleotide can comprise at least 538, 600, 700, 751, 800, 850, 900, 950, 1000, 1200, 1300, 1400, 1500 or 1600 contiguous nucleotides of SEQ ID NO:5, at least 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, or 50 contiguous nucleotides selected from nucleotides 1-946, at least 13 contiguous nucleotides selected from nucleotides 1-1039 of SEQ ID NO:5, or the complements thereof.

[0065] Yet another polynucleotide of the invention has the nucleotide sequence shown in SEQ ID NO:7 and is designated BMS118. BMS118 cDNA represents a transcript of 1499 nucleotides with a translation start codon (ATG) at position 140, a translation stop codon (TAA) at position 1358, a polyadenylation signal (AATAAA) (SEQ ID NO:45) at position 1463, and a poly(A) tail at position 1482. The DNA sequence between nucleotides 140 and 1357 encodes a polypeptide of 406 amino acid residues (SEQ ID NO:8). The potential signal peptide of the BMS118 protein is located in the first 29 amino acids. A BMS118 polynucleotide can comprise at least 522, 550, 600, 651, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, or 1450 contiguous nucleotides of SEQ ID NO:7, at least 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, or 50 contiguous nucleotides selected from nucleotides 1-913 of SEQ ID NO:7, or the complements thereof.

[0066] Another polynucleotide of the invention has the nucleotide sequence shown in SEQ ID NO:9 and is designated BMS164. BMS164 cDNA represents a transcript of 1272 nucleotides with a translation start codon (ATG) at position 313 and a translation stop codon (TAG) at position 1186. The DNA sequence between nucleotides 313 and 1 185 encodes a polypeptide of 291 amino acid residues (SEQ ID NO:10). A BMS164 polynucleotide can comprise at least 317, 400, 484, 500, 600, 700, 800, 900, 1000, 1100, or 1200 contiguous nucleotides of SEQ ID NO:9, at least 183 contiguous nucleotides selected from nucleotides 1-984 of SEQ ID NO:9, or at least 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, or 50 contiguous nucleotides selected from nucleotides 1-216 or 379-812 of SEQ ID NO:9, or the complements thereof.

[0067] Another polynucleotide of the invention, BMS192, has the nucleotide sequence shown in SEQ ID NO:11. BMS192 cDNA represents a transcript of 1585 nucleotides with a translation start codon (ATG) at position 41, a translation stop codon (TGA) at position 1190, a polyadenylation signal (AATAAA) (SEQ ID NO:45) at position 1439, and a poly(A) tail at position 1574. The DNA sequence between nucleotides 41 and 1189 encodes apolypeptide of 383 amino acid residues (SEQ ID NO:12). The potential signal peptide of the BMS192 protein is located in the first 19 amino acids. A BMS192 polynucleotide can comprise at least 289, 300, 400, 500, 594, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, or 1500 contiguous nucleotides of SEQ ID NO:11, at least 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, or 50 contiguous nucleotides selected from nucleotides 1-585 or 853-1120 of SEQ ID NO:11, or the complements thereof.

[0068] Another polynucleotide of the invention, BMS227, has the nucleotide sequence shown in SEQ ID NO:13. BMS227 cDNA represents a transcript of 1071 nucleotides with a translation start codon (ATG) at position 151, a translation stop codon (TGA) at position 934, a polyadenylation signal (AATAAA) (SEQ ID NO:45) at position 1018, and a poly(A) tail at position 1053. The DNA sequence between nucleotides 151 and 933 encodes a polypeptide of 261 amino acid residues (SEQ ID NO:14). The potential signal peptide of the BMS227 protein is located in the first 32 amino acids. A BMS227 polynucleotide can comprise 275, 300, 400, 500, 592, 600, 700, 800, 900, or 1000 contiguous nucleotides of SEQ ID NO:13, at least 11, 12, 13,14, 15, 20, 25,30, 35, 40, or 50 contiguous nucleotides selected from nucleotides 1-294 of SEQ ID NO:13, or the complements thereof.

[0069] Yet another polynucleotide of the invention is designated BMS115. The nucleotide sequence of BMS115 is shown in SEQ ID NO:15. BMS115 cDNA represents a transcript of 2520 nucleotides with a translation start codon (ATG) at position 1, a translation stop codon at position 1666, a polyadenylation signal (AATAAA) (SEQ ID NO:45) at position 2470, and a poly(A) tail at position 2503. The DNA sequence between nucleotides 1 and 1665 encodes a protein of 555 amino acids, as shown in SEQ ID NO:16. A potential signal peptide is located in the first 31 amino acid residues. A BMS115 polynucleotide can comprise at least 537, 600, 700, 800, 900, 1000, 1250, 1500, 1750, 2000, 2250, or 2500 contiguous nucleotides of SEQ ID NO:15, at least 294 contiguous nucleotides selected from nucleotides 1-1889 of SEQ ID NO:15, at least 171 contiguous nucleotides selected from nucleotides 318-1766 of SEQ ID NO:15, or at least 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, or 50 contiguous nucleotides selected from nucleotides 1-42, 478-908, or 1059-1078 of SEQ ID NO:15, or the complements thereof.

[0070] Yet another polynucleotide of the invention is designated BMS143. The nucleotide sequence of BMS143 is shown in SEQ ID NO:17. BMS143 cDNA represents a transcript of 1245 nucleotides with a translation start codon (ATG) at position 89, a translation stop codon at position 785, a polyadenylation signal (AATAAA) (SEQ ID NO:45) at position 1199, and a poly(A) tail at position 1231. The DNA sequence between nucleotides 89 and 784 encodes a protein of 232 amino acids, as shown in SEQ ID NO:18. A potential signal peptide is located in the first 54 amino acid residues. A BMS143 polynucleotide can comprise at least 205, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, or 1200 contiguous nucleotides of SEQ ID NO:17, or the complements thereof.

[0071] Yet another polynucleotide of the invention is designated BMS155. The nucleotide sequence of BMS155 is shown in SEQ ID NO:19. BMS155 cDNA represents a transcript of 1030 nucleotides with a translation start codon (ATG) at position 4, a translation stop codon at position 451, a polyadenylation signal (AATAAA) (SEQ ID NO:45) at position 987, and a poly(A) tail at position 1016. The DNA sequence between nucleotides 4 and 450 encodes a protein of 149 amino acids, as shown in SEQ ID NO:20. A potential signal peptide is located in the first 47 amino acid residues. A BMS155 polynucleotide can comprise at least 440, 500, 600, 700, 800, 900, or 1000 contiguous nucleotides of SEQ ID NO:19 or the complements thereof.

[0072] Yet another polynucleotide of the invention is designated BMS208. The nucleotide sequence of BMS208 is shown in SEQ ID NO:21. BMS208 cDNA represents a transcript of 1563 nucleotides with a translation start codon (ATG) at position 255, a translation stop codon at position 756, a polyadenylation signal (AATAAA) (SEQ ID NO:45) at position 1531, and a poly(A) tail at position 1550. The DNA sequence between nucleotides 255 and 755 encodes a protein of 167 amino acids, as shown in SEQ ID NO:22. A potential signal peptide is located in the first 62 amino acid residues. A BMS208 polynucleotide can comprise at least 451, 500, 600, 750, 1000, 1250, or 1500 contiguous nucleotides of SEQ ID NO:21, at least 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, or 50 contiguous nucleotides selected from nucleotides 1-121 or 474-592 of SEQ ID NO:21, or the complements thereof.

[0073] Yet another polynucleotide of the invention is designated BMS235. The nucleotide sequence of BMS235 is shown in SEQ ID NO:23. BMS235 cDNA represents a transcript of 2590 nucleotides with a translation start codon (ATG) at position 29, a translation stop codon at position 872, and a poly(A) tail at position 1526. The DNA sequence between nucleotides 29 and 871 encodes a protein of 281 amino acids, as shown in SEQ ID NO:24. A potential signal peptide is located in the first 25 amino acid residues. A BMS235 polynucleotide can comprise at least 351 contiguous nucleotides of SEQ ID NO:23, at least 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, or 50 contiguous nucleotides selected from nucleotides 1-612, 611-719, 713-830, or 830-1933 of SEQ ID NO:23, at least 21 contiguous nucleotides selected from nucleotides 1-1943 of SEQ ID NO:23, or the complements thereof.

[0074] Yet another polynucleotide of the invention is designated BMS240. The nucleotide sequence of BMS240 is shown in SEQ ID NO:25. BMS240 cDNA represents a transcript of 1668 nucleotides with a translation start codon (ATG) at position 99, a translation stop codon at position 807, a polyadenylation signal (AATAAA) (SEQ ID NO:45) at position 1626, and a poly(A) tail at position 1655. The DNA sequence between nucleotides 99 and 806 encodes a protein of 236 amino acids, as shown in SEQ ID NO:26. A BMS240 polynucleotide can comprise at least 492, 500, 600, 750, 1000, 1250, 1500, or 1600 contiguous nucleotides of SEQ ID NO:25, at least 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, or 50 contiguous nucleotides selected from nucleotides 758-847 of SEQ ID NO:25, or the complements thereof.

[0075] Yet another polynucleotide of the invention is designated BMS53. The nucleotide sequence of BMS53 is shown in SEQ ID NO:27. BMS53 cDNA represents a transcript of 1697 nucleotides with a translation start codon (ATG) at position 29, a translation stop codon at position 1427, a polyadenylation signal (ATTAAA) (SEQ ID NO:46) at position 1659, and a poly(A) tail at position 1682. The DNA sequence between nucleotides 29 and 1426 encodes a polypeptide of 466 amino acid residues, as shown in SEQ ID NO:28. A BMS53 polynucleotide can comprise at least 1024, 1100, 1200, 1300, 1400, 1500, or 1600 contiguous nucleotide of SEQ ID NO:27 or the complements thereof.

[0076] Yet another polynucleotide of the invention is designated BMS100. The nucleotide sequence of BMS100 is shown in SEQ ID NO:29. BMS100 cDNA represents a transcript of 1830 nucleotides with a translation start codon (ATG) at position 218, a translation stop codon at position 851, a polyadenylation signal (AATAAA) (SEQ ID NO:35) at position 1792, and a poly(A) tail at position 1811. The DNA sequence between nucleotides 218 and 850 encodes a protein of 211 amino acids, as shown in SEQ ID NO:30. A potential signal peptide is located in the first 18 amino acid residues. A BMS100 polynucleotide can comprise at least 347, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, or 1800 contiguous nucleotides of SEQ ID NO:29, at least 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, or 50 contiguous nucleotides selected from nucleotides 548-601 of SEQ ID NO:29, or the complements thereof.

[0077] Yet another polynucleotide of the invention is designated BMS199. The nucleotide sequence of BMS199 is shown in SEQ ID NO:31. BMS199 cDNA represents a transcript of 1102 nucleotides with a translation start codon (ATG) at position 267, a translation stop codon at position 990, a polyadenylation signal (AATAAA) (SEQ ID NO:45) at position 1072, and a poly(A) tail at position 1089. The DNA sequence between nucleotides 267 and 989 encodes a protein of 241 amino acids, as shown in SEQ ID NO:32. A potential signal peptide is located in the first 32 amino acid residues. A BMS199 polynucleotide can comprise at least 394, 400, 500, 600, 700, 800, 900, 1000, or 1100 contiguous nucleotides of SEQ ID NO:31, at least 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, or 50 contiguous nucleotides selected from nucleotides 1-361 or 1083-1102 of SEQ ID NO:31, or the complements thereof.

[0078] Yet another polynucleotide of the invention is designated BMS206. The nucleotide sequence of BMS206 is shown in SEQ ID NO:33. BMS206 cDNA represents a transcript of 966 nucleotides with a translation start codon (ATG) at position 36, a translation stop codon at position 585, a polyadenylation signal (AATAAA) (SEQ ID NO:45) at position 920, and a poly(A) tail at position 949. The DNA sequence between nucleotides 36 and 584 encodes a protein of 183 amino acids, as shown in SEQ ID NO:34. A BMS206 polynucleotide can comprise at least 492, 500, 600, 700, 800, or 900 contiguous nucleotides of SEQ ID NO:33 or the complements thereof.

[0079] Yet another polynucleotide of the invention is designated BMS242. The nucleotide sequence of BMS242 is shown in SEQ ID NO:35. BMS242 cDNA represents a transcript of 1570 nucleotides with a translation start codon (ATG) at position 76, a translation stop codon at position 1030, and a poly (1) tail at position 1562. The DNA sequence between nucleotides 76 and 1029 encodes a protein of 318 amino acid residues, as shown in SEQ ID NO:36. A BMS242 polynucleotide can comprise at least 510, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, or 1500 contiguous nucleotides of SEQ ID NO:35, at least 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, or 50 contiguous nucleotides selected from nucleotides 1-502 or 505-631 of SEQ ID NO:35, or the complements thereof.

[0080] Yet another polynucleotide of the invention is termed BMS37. The nucleotide sequence of BMS37 is shown in SEQ ID NO:37. BMS37 cDNA represents a transcript of 1542 nucleotides with a translation start codon (ATG) at position 121, a translation stop codon at position 1105, a polyadenylation signal (AATAAA) (SEQ ID NO:45) at position 1508, and a poly(A) tail at position 1526. The DNA sequence between nucleotides 121 and 1104 encodes a protein of 328 amino acid residues, as shown in SEQ ID NO:38. The potential signal peptide the BMS37 protein is located in the first 20 amino acids. A BMS37 polynucleotide can comprise at least 392, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, or 1500 contiguous nucleotides of SEQ ID NO:37, at least 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, or 50 contiguous nucleotides selected from nucleotides 1-502 or 505-631 of SEQ ID NO:37, or the complements thereof.

[0081] Yet another polynucleotide of the invention is designated BMS42. The nucleotide sequence of BMS42 is shown in SEQ ID NO:39. BMS42 cDNA represents a transcript of 1990 nucleotides with a translation start codon (ATG) at position 104, a translation stop codon at position 1615, a polyadenylation signal (AATAAA) (SEQ ID NO:45) at position 1952, and a poly(A) tail at position 1971. The DNA sequence between nucleotides 104 and 1614 encodes a protein of 504 amino acids, as shown in SEQ ID NO:40. A potential signal peptide is located in the first 67 amino acids. A BMS42 polynucleotides can comprise at least 559, 600, 700, 800, 900, 10000, 1250, 1500, 1750, 1800, or 1900 contiguous nucleotides of SEQ ID NO:39, at least 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, or 50 contiguous nucleotides selected from nucleotides 1-92 of SEQ ID NO:39, or the complements thereof.

[0082] Yet another polynucleotide of the invention is designated BMS60. The nucleotide sequence of BMS60 is shown in SEQ ID NO:41. BMS60 cDNA represents a transcript of 684 nucleotides with a translation start codon (ATG) at position 7, a translation stop codon at position 445, a polyadenylation signal (AATAAA) (SEQ ID NO:45) at position 644, and a poly(A) tail at position 667. The DNA sequence between nucleotides 7 and 444 encodes a protein of 146 amino acid residues, as shown in SEQ ID NO:42. A potential signal peptide is located in the first 20 amino acids. A BMS60 polynucleotide can comprise at least 254, 300, 350, 400, 450, 500, 550, 600, or 650 contiguous nucleotides of SEQ ID NO:41, at least 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, or 50 contiguous nucleotides selected from nucleotides 1-34 or 55-110 of SEQ ID NO:41, or the complements thereof.

[0083] Yet another polynucleotide of the invention is designated BMS61. The nucleotide sequence of BMS61 is shown in SEQ ID NO:43. BMS61 cDNA represents a transcript of 1152 nucleotide with a translation start codon (ATG) at position 276, a translation stop codon at position 795, and a poly(A) tail at position 1150. The DNA sequence between nucleotides 276 and 794 encodes a protein of 173 amino acid residues, as shown in SEQ ID NO:44. A BMS61 polynucleotide can comprise at least 103, 200, 300, 400, 500, 600, 700, 800, 900, 1000 or 1100 contiguous nucleotides of SEQ ID NO:43, at least 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, or 50 contiguous nucleotides selected from nucleotides 1-280, 270-319, 378-423, 414-492, 532-570, or 1086-1152 of SEQ ID NO:43, or the complements thereof.

[0084] The present invention provides isolated genes which comprise the coding sequences disclosed herein. The genes can be isolated in accordance with known methods using the sequence information disclosed herein. Such methods include the preparation of probes or primers from the disclosed sequence information for identification and/or amplification of genes in appropriate genomic libraries or other sources of genomic materials.

[0085] The invention also provides means of altering the expression of genes which have the coding sequences disclosed herein. In one embodiment of the invention, expression of an endogenous gene having a coding sequence as shown in SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, or 43 in a cell can be altered by introducing in frame with the endogenous gene a DNA construct comprising a transcription unit by homologous recombination to form a homologously recombinant cell comprising the transcription unit. The transcription unit comprises a targeting sequence, a regulatory sequence, an exon, and an unpaired splice donor site. This method of affecting endogenous gene expression is taught in U.S. Pat. No. 5,641,670.

[0086] The targeting sequence is a segment of at least 10, 12, 15, 20, or 50 contiguous nucleotides selected from the nucleotide sequences shown in SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, and 43. The transcription unit is located upstream to a coding sequence of the endogenous gene. The exogenous regulatory sequence directs transcription of the coding sequence of the gene.

[0087] In another embodiment of the invention, expression of a gene with a coding sequence as shown in SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, or 43 is decreased using a ribozyme, an RNA molecule with catalytic activity. See, e.g., Cech, 1987, Science 236: 1532-1539; Cech, 1990, Ann. Rev. Biochem. 59:543-568; Cech, 1992, Curr. Opin. Struct. Biol. 2: 605-609; Couture and Stinchcomb, 1996, Trends Genet. 12: 510-515. Ribozymes can be used to inhibit gene function by cleaving an RNA sequence, as is known in the art (e.g., Haseloff et al., U.S. Pat. No. 5,641,673).

[0088] The coding sequences disclosed herein can be used to generate a ribozyme which will specifically bind to the corresponding mRNA. Methods of designing and constructing ribozymes which can cleave other RNA molecules in trans in a highly sequence specific manner have been developed and described in the art (see Haseloff et al., Nature 334:585-591, 1988). For example, the cleavage activity of ribozymes can be targeted to specific RNAs by engineering a discrete “hybridization” region into the ribozyme. The hybridization region contains a sequence complementary to the target RNA and thus specifically hybridizes with the target (see, for example, Gerlach et al., EP 321,201). Longer complementary sequences can be used to increase the affinity of the hybridization sequence for the target. The hybridizing and cleavage regions of the ribozyme can be integrally related; thus, upon hybridizing to the target RNA through the complementary regions, the catalytic region of the ribozyme can cleave the target.

[0089] Ribozymes can be introduced into cells as part of a DNA construct, as is known in the art. The DNA construct can also include transcriptional regulatory elements, such as a promoter element, an enhancer or UAS element, and a transcriptional terminator signal, for controlling transcription of the ribozyme in the cells.

[0090] Mechanical methods, such as microinjection, liposome-mediated transfection, electroporation, or calcium phosphate precipitation, can be used to introduce the ribozyme-containing DNA construct into cells in order to decrease gene expression. Alternatively, if it is desired that the cells stably retain the DNA construct, it can be supplied on a plasmid and maintained as a separate element or integrated into the genome of the cells, as is known in the art.

[0091] Expression of a gene with a coding sequence as shown in SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, or 43 can also be altered using an antisense oligonucleotide. The sequence of the antisense oligonucleotide is complementary to at least a portion of a coding sequence disclosed herein. Preferably, the antisense oligonucleotide is at least six nucleotides in length, but can be at least 8, 11, 12, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides long. Longer sequences, such as the complement of the nucleotide sequences shown in SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, or 43, can also be used. Antisense oligonucleotides can be provided in a construct of the invention and introduced into cells using transfection techniques known in the art.

[0092] Antisense oligonucleotides can be composed of deoxyribonucleotides, ribonucleotides, or a combination of both. Oligonucleotides can be synthesized manually or by an automated synthesizer, by covalently linking the 5′ end of one nucleotide with the 3′ end of another nucleotide with non-phosphodiester internucleotide linkages such alkylphosphonates, phosphorothioates, phosphorodithioates, alkylphosphonothioates, alkylphosphonates, phosphoramidates, phosphate esters, carbamates, acetamidate, carboxymethyl esters, carbonates, and phosphate triesters. See Brown, 1994, Meth. Mol. Biol. 20:1-8; Sonveaux, 1994, Meth. Mol. Biol. 26:1-72; Uhlmann et al., 1990, Chem. Rev. 90:543-583.

[0093] Precise complementarity is not required for successful duplex formation between an antisense molecule and its complementary coding sequence. Antisense molecules which comprise, for example, 2, 3, 4, or 5 or more stretches of contiguous nucleotides which are precisely complementary to a coding sequence of the invention, each separated by a stretch of contiguous nucleotides which are not complementary to adjacent coding sequences, can provide targeting specificity for mRNA. Preferably, each stretch of contiguous nucleotides is at least 4, 5, 6, 7, or 8 or more nucleotides in length. Non-complementary intervening sequences are preferably 1, 2, 3, or 4 nucleotides in length. One skilled in the art can easily use the calculated melting point of an antisense-sense pair to determine the degree of mismatching which will be tolerated between a particular antisense oligonucleotide and a particular coding sequence of the invention.

[0094] Antisense oligonucleotides can be modified without affecting their ability to hybridize to a coding sequence of the invention. These modifications can be internal or at one or both ends of the antisense oligonucleotide. For example, internucleoside phosphate linkages can be modified by adding cholesteryl or diamine moieties with varying numbers of carbon residues between the amino groups and terminal ribose. Modified bases and/or sugars, such as arabinose instead of ribose, or a 3′, 5′-substituted oligonucleotide in which the 3′ hydroxyl group or the 5′ phosphate group are substituted, can also be employed in a modified antisense oligonucleotide. These modified oligonucleotides can be prepared by methods well known in the art. Agrawal et al., Trends Biotechnol. 10:152-158, 1992; Uhlmann et al., Chem. Rev. 90:543-584, 1990; Uhlmann et al., Tetrahedron. Lett. 215:3539-3542, 1987.

[0095] Antibodies of the invention can also be used to decrease the function of proteins of the invention. Specific antibodies bind to a protein of the invention to prevent the protein from functioning in the cell. Polynucleotides encoding single-chain antibodies of the invention can be introduced into cells using standard transfection techniques. Alternatively, therapeutic antibodies of the invention can be targeted to a particular cell type, for example, by binding an antibody to a coupling molecule which is specific for both the antibody and the target, as disclosed in WO 95/08577. The coupling molecule can comprise immunoglobulin binding domains.

[0096] Proteins of the invention comprise the amino acid sequences shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and 44. Protein or polypeptide fragments which are capable of exhibiting biological activity are also encompassed by the present invention.

[0097] Non-naturally occurring protein variants which retain substantially the same biological activities as naturally occurring proteins of the invention are also included here. Preferably, naturally or non-naturally occurring protein variants have amino acid sequences which are at least 65%, 75%, 85%, 90%, or 95% identical to the amino acid sequences shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and 44 are secreted proteins, and have similar biological properties. More preferably, the molecules are 98% identical. Percent identity can be determined using computer programs which use the Smith-Waterman algorithm using an affine gap search with the following parameters: a gap open penalty of 12 and a gap extension penalty of 1.

[0098] Guidance in determining which amino acid residues may be substituted, inserted, or deleted without abolishing biological or immunological activity may be found using computer programs well known in the art, such as DNASTAR software. Preferably, amino acid changes in protein variants or derivatives are conservative amino acid changes, i.e., substitutions of similarly charged or uncharged amino acids. A conservative amino acid change involves substitution of one of a family of amino acids which are related in their side chains. Naturally occurring amino acids are generally divided into four families: acidic (aspartate, glutamate), basic (lysine, arginine, histidine), non-polar (alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), and uncharged polar (glycine, asparagine, glutamine, cystine, serine, threonine, tyrosine) amino acids. Phenylalanine, tryptophan, and tyrosine are sometimes classified jointly as aromatic amino acids. It is reasonable to expect that an isolated replacement of a leucine with an isoleucine or valine, an aspartate with a glutamate, a threonine with a serine, or a similar replacement of an amino acid with a structurally related amino acid will not have a major effect on the biological properties of the resulting protein variant.

[0099] Variants of proteins of the invention include glycosylated forms, aggregative conjugates with other molecules, and covalent conjugates with unrelated chemical moieties. Variants of the invention also include allelic variants, species variants, and muteins. Truncations or deletions of regions which do not affect the properties or functions of proteins of the invention are also variants. Covalent variants can be prepared by linkage of functionalities to groups which are found in the amino acid chain or at the N- or C-terminal residue, as is known in the art.

[0100] The invention also provides polypeptide fragments of the disclosed secreted proteins. Polypeptides of the invention comprise less than all of the amino acid sequences shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, or 42 in the same primary order as found in the full-length amino acid sequences. For example, polypeptides of the invention can comprise at least 95, 100, 120, 130, or 140 contiguous amino acids of SEQ ID NO:2.

[0101] Other polypeptides of the invention can comprise at least 6, 8, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 101, 110, 120, 130, 150, 160, 170, or 180 contiguous amino acids of SEQ ID NO:4.

[0102] Yet other polypeptides of the invention can comprise at least 14, 15, 16, 18, 20, 25, or 30 contiguous amino acids selected from amino acids 1-312 of SEQ ID NO:6 or at least 75, 100, 125, 150, 175, 179, 200, 225, 250, 275, 300, 325, or 350 contiguous amino acids of SEQ ID NO:6.

[0103] Even other polypeptides of the invention can comprise at least 17, 18, 19, 20, 25, or 30 contiguous amino acids selected from amino acids 1-287 of SEQ ID NO:8 or at least 136, 140, 150, 150, 179, 200, 250, 300, 350, or 400 contiguous amino acids selected from SEQ ID NO:8.

[0104] Still other polypeptides of the invention can comprise at least 31, 32, 35, 40, or 45 contiguous amino acids selected from amino acids 1-238 of SEQ ID NO:10 or at least 82, 85, 100, 132, 150, 200, 225, 250, or 275 contiguous amino acids of SEQ ID NO:10.

[0105] Other polypeptides of the invention can comprise at least 6, 7, 8, 9, 10, 15, or 20 contiguous amino acids selected from amino acids 1-184 or 270-362 of SEQ ID NO: 12, at least 8, 9, 10, 12, 15, 20, or 25 contiguous amino acids selected from amino acids 268-364 of SEQ ID NO:12, at least 27, 30, 35, or 40 contiguous amino acids selected from amino acids 250-383 of SEQ ID NO:12, or at least 96, 100, 150, 200, 250, 300, or 350 contiguous amino acids selected from SEQ ID NO:12.

[0106] Yet other polypeptides of the invention can comprise at least 6, 7, 8, 9, 10, 12, 15, or 20 contiguous amino acids selected from amino acids 1-111 or 204-261 of SEQ ID NO:14, at least 17, 18, 20, 25, or 30 contiguous amino acids selected from amino acids 1-150 of SEQ ID NO:14, at least 75, 80, 100, 104, 125, 150, 175, 200, 225, or 250 contiguous amino acids of SEQ ID NO:14.

[0107] Even other polypeptides of the invention can comprise at least 8, 10, 12, 14, 16, 20, 30, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, or 550 contiguous amino acids of SEQ ID NO:16.

[0108] Still other polypeptides of the invention can comprise at least 39, 40, 45, 46, or 50 contiguous amino acids selected from amino acids 13-232 of SEQ ID NO:18 or at least 46, 50, 55, 60, 75, 100, 125, 150, 175, 200, or 225 contiguous amino acids of SEQ ID NO:18.

[0109] Other polypeptides of the invention can comprise at least 6, 8, 10, 12, 15, 20, 25, 30, 50, 75, 100, 125, or 140 contiguous amino acids from SEQ ID NO:20.

[0110] Yet other polypeptides of the invention can comprise at least 7, 8, 10, 12, 15, 20, 25, 30, 50, 75, 100, 125, 150, or 160 contiguous amino acids from SEQ ID NO:22.

[0111] Even other polypeptides of the invention comprise at least 7, 8, 10, 12, 15, 20, 25, 30, 50, 75, 100, 125, 150, 175, 200, 225, 250, or 275 contiguous amino acids of SEQ ID NO:24.

[0112] Still other polypeptides of the invention comprise at least 11, 12, 15, 18, 20, 25, 30, 35, 50, 75, 100, 125, 150, 175, 200, or 225 contiguous amino acids of SEQ ID NO:26.

[0113] Other polypeptides of the invention comprise at least 6, 8, 10, 12, 15, or 20 contiguous amino acids selected from amino acids 1-31 of SEQ ID NO:28 or at least 257, 260, 270, 280, 290, 300, 325, 350, 375, 400, 425, or 450 contiguous amino acids of SEQ ID NO:28.

[0114] Yet other polypeptides of the invention comprise at least 6, 8, 10, 12, 15, 18, 20, 25, 30, 50, 75, 100, 125, 150, 175, or 200 contiguous amino acids of SEQ ID NO:30.

[0115] Even other polypeptides of the invention comprise at least 6, 8, 10, 12, 15, or 20 contiguous amino acids selected from amino acids 1-65 of SEQ ID NO:32 or at least 117, 120, 150, 175, 200, or 225 contiguous amino acids of SEQ ID NO:32.

[0116] Still other polypeptides of the invention comprise at least 6, 8, 10, 12, 15, 20, 25, 30, 50, 75, 100, 125, 150, or 175 contiguous amino acids of SEQ ID NO:34.

[0117] Other polypeptides of the invention comprise at least 14, 15, 18, 20, 25, 30, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, or 300 contiguous amino acids of SEQ ID NO:36.

[0118] Yet other polypeptides of the invention comprise at least 19, 20, 25, 30, 35, 40, 50, 75, 100, 125, 150, 175, 200, 224, 250, 275, 300, or 325 contiguous amino acids of SEQ ID NO:38.

[0119] Even other polypeptides of the invention comprise at least 8, 10, 12, 15, 18, 20, 25, 30, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or 500 contiguous amino acids of SEQ ID NO:40.

[0120] Still other polypeptides of the invention comprise at least 7, 8, 10, 12, 15, 20, 30, 50, 75, 100, or 125 contiguous amino acids of SEQ ID NO:42.

[0121] Other polypeptides of the invention comprise at least 10, 12, 15, 20, 25, 30, 50, 75, 100, 125, 150, or 170 contiguous amino acids of SEQ ID NO:44.

[0122] Polypeptides can be linear or can be cyclized using known methods, for example, as described in Saragovi et al., Bio/Technology 10, 773-778 (1992) or McDowell et al., J. Amer. Chem. Soc. 114, 9245-9253 (1992). Polypeptides can optionally be fused to carrier molecules such as immunoglobulins and used, for example, to increase the number of protein binding sites in a molecule or a molecular complex. Polypeptide fragments of the protein can be fused through linker sequences to the Fc portion of an immunoglobulin. Fusion of polypeptide fragments to the Fc portions of an IgG molecule can provide a bivalent form of a protein. Other immunoglobulin Fc portions, for example, IgM or IgA, can be used to provide multivalent forms of a protein.

[0123] Receptors or other membrane-bound proteins of the invention can be solubilized by deleting part of all of the intracellular and transmembrane domains of the protein, such that the protein can be fully secreted from a cell in which it is expressed. Intracellular and transmembrane domains of proteins of the invention can be identified using known techniques for determination of such domains from sequence information.

[0124] The invention also provides species homologs of the disclosed polynucleotides and proteins. Species homologs can be isolated and identified, for example, by making suitable probes or primers from the sequences disclosed herein and screening a suitable nucleic acid source from the desired species. The invention also encompasses allelic variants of the disclosed polynucleotides or proteins. Allelic variants are naturally-occurring alternative forms of polynucleotides which encode proteins which are identical, homologous, or related to those encoded by the polynucleotides shown in SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, and 43.

[0125] Proteins of the invention can be prepared by culturing transformed host cells under culture conditions suitable for expression of the recombinant protein. If a protein of the invention is produced in a yeast or bacterial expression system, it may be necessary to modify the protein, for example, by phosphorylation or glycosylation of appropriate sites, in order to obtain the protein in a functional form. Such covalent attachments can be made using known chemical or enzymatic methods. The resulting expressed protein can then be purified from the culture (ie., from culture medium or cell extracts) using known purification techniques, such as size exclusion chromatography, ammonium sulfate fractionation, ion exchange chromatography, affinity chromatography, crystallization, electrofocusing, immunoprecipitation, immunoaffinity chromatography, and preparative gel electrophoresis.

[0126] A protein of the invention can optionally be expressed in a form which will facilitate purification. A protein can be expressed as a fusion protein with, for example, maltose binding protein (MBP), glutathione-S-transferase (GST), or thioredoxin (TRX). Kits for expression and purification of such fusion proteins are commercially available from New England BioLab (Beverly, Mass.), Pharmacia (Piscataway, N.J.) and In Vitrogen, respectively. Alternatively, a protein of the invention can be tagged with an epitope and subsequently purified using a specific antibody directed to the epitope. One such epitope, Flag, is commercially available from Kodak (New Haven, Conn.).

[0127] A protein of the invention can be expressed as a product of transgenic animals, e.g., as a component of the milk of transgenic cows, goats, pigs, or sheep which are characterized by somatic or germ cells containing a nucleotide sequence encoding the protein. Proteins of the invention can also be produced by known conventional chemical synthesis. Methods for constructing the proteins of the present invention by synthetic means, such as solid phase peptide synthesis, are well known in the art.

[0128] Fusion proteins comprising amino acid sequences of proteins of the invention can also be constructed. Fusion proteins are useful for generating antibodies against amino acid sequences and for use in various assay systems. For example, fusion proteins can be used to identify proteins which interact with proteins of the invention. Physical methods, such as protein affinity chromatography, or library-based assays for protein-protein interactions such as the yeast two-hybrid or phage display systems, can also be used for this purpose. Such methods are well known in the art and can also be used as drug screens.

[0129] A fusion protein of the invention comprises two protein segments fused together by means of a peptide bond. The first protein segment consists of at least 95, 100, 120, 130, or 140 contiguous amino acids of SEQ ID NO:2, at least 6, 8, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 101, 110, 120, 130, 150, 160, 170, or 180 contiguous amino acids of SEQ ID NO:4, at least 14, 15, 16, 18, 20, 25, or 30 contiguous amino acids selected from amino acids 1-312 of SEQ ID NO:6 or at least 75, 100, 125, 150, 175, 179, 200, 225, 250, 275, 300, 325, or 350 contiguous amino acids of SEQ ID NO:6, at least 17, 18, 19, 20, 25, or 30 contiguous amino acids selected from amino acids 1-287 of SEQ ID NO:8 or at least 136, 140, 150, 150, 179, 200, 250, 300, 350, or 400 contiguous amino acids selected from SEQ ID NO:8, at least 31, 32, 35, 40, or 45 contiguous amino acids selected from amino acids 1-238 of SEQ ID NO:10, or at least 82, 85, 100, 132, 150, 200, 225, 250, or 275 contiguous amino acids of SEQ ID NO:10, at least 6, 7, 8, 9, 10, 15, or 20 contiguous amino acids selected from amino acids 1-184 or 270-362 of SEQ ID NO:12, at least 8, 9, 10, 12, 15, 20, or 25 contiguous amino acids selected from amino acids 268-364 of SEQ ID NO:12, at least 27, 30, 35, or 40 contiguous amino acids selected from amino acids 250-383 of SEQ ID NO:12, or at least 96, 100, 150, 200, 250, 300, or 350 contiguous amino acids selected from SEQ ID NO:12, at least 6, 7, 8, 9, 10, 12, 15, or 20 contiguous amino acids selected from amino acids 1-111 or 204-261 of SEQ ID NO:14, at least 17, 18, 20, 25, or 30 contiguous amino acids selected from amino acids 1-150 of SEQ ID NO:14, at least 75, 80, 100, 104, 125, 150, 175, 200, 225, or 250 contiguous amino acids of SEQ ID NO:14, at least 8, 10, 12, 14, 16, 20, 30, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, or 550 contiguous amino acids of SEQ ID NO:16, at least 39, 40, 45, 46, or 50 contiguous amino acids selected from amino acids 13-232 of SEQ ID NO:18 or at least 46, 50, 55, 60, 75, 100, 125, 150, 175, 200, or 225 contiguous amino acids of SEQ ID NO:18, at least 6, 8, 10, 12, 15, 20, 25, 30, 50, 75, 100, 125, or 140 contiguous amino acids from SEQ ID NO:20, at least 7, 8, 10, 12, 15, 20, 25, 30, 50, 75, 100, 125, 150, or 160 contiguous amino acids from SEQ ID NO:22, at least 7, 8, 10, 12, 15, 20, 25, 30, 50, 75, 100, 125, 150, 175, 200, 225, 250, or 275 contiguous amino acids of SEQ ID NO:24, at least 11, 12, 15, 18, 20, 25, 30, 35, 50, 75, 100, 125, 150, 175, 200, or 225 contiguous amino acids of SEQ ID NO:26, at least 6, 8, 10, 12, 15, or 20 contiguous amino acids selected from amino acids 1-31 of SEQ ID NO:28 or at least 257, 260, 270, 280, 290, 300, 325, 350, 375, 400, 425, or 450 contiguous amino acids of SEQ ID NO:28, at least 6, 8, 10, 12, 15, 18, 20, 25, 30, 50, 75, 100, 125, 150, 175, or 200 contiguous amino acids of SEQ ID NO:30, at least 6, 8, 10, 12, 15, or 20 contiguous amino acids selected from amino acids 1-65 of SEQ ID NO:32 or at least 117, 120, 150, 175, 200, or 225 contiguous amino acids of SEQ ID NO:32, at least 6, 8, 10, 12, 15, 20, 25, 30, 50, 75, 100, 125, 150, or 175 contiguous amino acids of SEQ ID NO:34, at least 14, 15, 18, 20, 25, 30, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, or 300 contiguous amino acids of SEQ ID NO:36, at least 19, 20, 25, 30, 35, 40, 50, 75, 100, 125, 150, 175, 200, 224, 250, 275, 300, or 325 contiguous amino acids of SEQ ID NO:38, at least 8, 10, 12, 15, 18, 20, 25, 30, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or 500 contiguous amino acids of SEQ ID NO:40, at least 7, 8, 10, 12, 15, 20, 30, 50, 75, 100, or 125 contiguous amino acids of SEQ ID NO:42, at least 10, 12, 15, 20, 25, 30, 50, 75, 100, 125, 150, or 170 contiguous amino acids of SEQ ID NO:44. The amino acids can also be selected from biologically active variants of those sequences The first protein segment can also be a full-length protein as shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, or 44. The first protein segment can be N-terminal or C-terminal, as is convenient.

[0130] The second protein segment can be a full-length protein or a protein fragment or polypeptide. Proteins commonly used in fusion protein construction include β-galactosidase, β-glucuronidase, green fluorescent protein (GFP), autofluorescent proteins, including blue fluorescent protein (BFP), glutathione-S-transferase (GST), luciferase, horseradish peroxidase (HRP), and chloramphenicol acetyltransferase (CAT). Epitope tags can be used in fusion protein constructions, including histidine (His) tags, FLAG tags, influenza hemagglutinin (HA) tags, Myc tags, VSV-G tags, and thioredoxin (Trx) tags. Other fusion constructions can include maltose binding protein (MBP), S-tag, Lex A DNA binding domain (DBD) fusions, GAL4 DNA binding domain fusions, and herpes simplex virus (HSV) BP16 protein fusions.

[0131] Fusion proteins of the invention can be made by covalently linking the first and second protein segments or by standard procedures in the art of molecular biology. Recombinant DNA methods can be used to prepare fusion proteins, for example, by making a DNA construct which comprises coding sequences selected from SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, or 43 in proper reading frame with nucleotides encoding the second protein segment and expressing the DNA construct in a host cell, as is known in the art. Many kits for constructing fusion proteins are available from companies which supply research labs with tools for experiments, including, for example, Promega Corporation (Madison, Wis.), Stratagene (La Jolla, Calif.), Clontech (Mountain View, Calif.), Santa Cruz Biotechnology (Santa Cruz, Calif.), MBL International Corporation (MIC; Watertown, Mass.), and Quantum Biotechnologies (Montreal, Canada; 1-888-DNA-KITS).

[0132] Isolated proteins, polypeptides, biologically active variants, or fusion proteins can be used as immunogens, to obtain a preparation of antibodies which specifically bind to epitopes of the secreted proteins disclosed herein. The entire protein or fragments of the protein can be used as an immunogen, optionally conjugated to a hapten, such as keyhole limpet hemocyanin.

[0133] The antibodies can be used, inter alia, to detect proteins of the invention in human tissue or in fractions thereof. The antibodies can also be used to detect the presence of mutations in the genes encoding these proteins which result in under- or over-expression of proteins of the invention or in expression of a secreted protein with altered size or electrophoretic mobility. By binding to a protein of the invention, antibodies can also alter the functions of the protein.

[0134] Antibodies which specifically bind to a protein of the invention can be useful diagnostic agents. Antibodies can also be used to treat conditions associated with the protein, including forms of cancer in which abnormal expression of the protein is involved. In the case of neoplastic cells, antibodies which specifically bind to the protein can be useful for suppressing the metastatic spread of the neoplastic cells, which can be mediated by the protein.

[0135] Antibodies which specifically bind to epitopes of the secreted proteins, polypeptides, fusion proteins, or biologically active variants disclosed herein can be used in immunochemical assays, including but not limited to Western blots, ELISAs, radioimmunoassays, immunohistochemical assays, immunoprecipitations, or other immunochemical assays known in the art. Typically, antibodies of the invention provide a detection signal at least 5-, 10-, or 20-fold higher than a detection signal provided with other proteins when used in such immunochemical assays. Preferably, antibodies which specifically bind to epitopes of a particular secreted protein do not detect other proteins in immunochemical assays and can immunoprecipitate that protein or polypeptide fragments of the protein from solution.

[0136] Specific antibodies specifically bind to epitopes present in a secreted protein having one of the amino acid sequences shown in SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, or 44 or to biologically active variants of those sequences. Typically, at least 6, 8, 10, or 12 contiguous amino acids are required to form an epitope. However, epitopes which involve non-contiguous amino acids may require more, e.g., at least 15, 25, or 50 amino acids. Preferably, the epitopes are not present in other human proteins.

[0137] Epitopes of proteins of the invention which are particularly antigenic can be selected, for example, by routine screening of polypeptide fragments of the protein for antigenicity or by applying a theoretical method for selecting antigenic regions of a protein to the amino acid sequences disclosed herein. Such methods are taught, for example, in Hopp and Wood, Proc. Natl. Acad. Sci. U.S.A. 78, 3824-28 (1981), Hopp and Wood, Mol. Immunol. 20, 483-89 (1983), and Sutcliffe et al., Science 219, 660-66 (1983).

[0138] Any type of antibody known in the art can be generated to bind specifically to epitopes of a secreted protein of the invention. For example, preparations of polyclonal and monoclonal antibodies can be made using standard methods which are well known in the art. Similarly, single-chain antibodies can also be prepared. Single-chain antibodies can be isolated, for example, from single-chain immunoglobulin display libraries, as is known in the art. The library is “panned” against amino acid sequences of a particular protein of the invention, and a number of single chain antibodies which bind with high-affinity to different epitopes of the protein can be isolated. Hayashi et al., 1995, Gene 160:129-30. Single-chain antibodies can also be constructed using a DNA amplification method, such as the polymerase chain reaction (PCR), using hybridoma cDNA as a template. Thirion et al., 1996, Eur. J. Cancer Prev. 5:507-11.

[0139] Single-chain antibodies can be mono- or bispecific, and can be bivalent or tetravalent. Construction of tetravalent, bispecific single-chain antibodies is taught, for example, in Coloma and Morrison, 1997, Nat. Biotechnol. 15:159-63. Construction of bivalent, bispecific single-chain antibodies is taught inter alia in Mallender and Voss, 1994, J. Biol. Chem. 269:199-206.

[0140] A nucleotide sequence encoding a single-chain antibody can be constructed using manual or automated nucleotide synthesis, cloned into an expression construct using standard recombinant DNA methods, and introduced into a cell to express the coding sequence, as described below. Alternatively, single-chain antibodies can be produced directly using, for example, filamentous phage technology. Verhaar et al., 1995, Int. J. Cancer 61:497-501; Nicholls et al., 1993, J. Immunol Meth. 165:81-91.

[0141] Monoclonal and other antibodies can also be “humanized” in order to prevent a patient from mounting an immune response against the antibody when it is used therapeutically. Such antibodies may be sufficiently similar in sequence to human antibodies to be used directly in therapy or may require alteration of a few key residues. Sequence differences between, for example, rodent antibodies and human sequences can be minimized by replacing residues which differ from those in the human sequences, for example, by site directed mutagenesis of individual residues, or by grafting of entire complementarity determining regions. Alternatively, one can produce humanized antibodies using recombinant methods, as described in GB2188638B. Antibodies which specifically bind to epitopes of a protein of the invention can contain antigen binding sites which are either partially or fully humanized, as disclosed in U.S. Pat. No. 5,565,332.

[0142] Other types of antibodies can be constructed and used in methods of the invention. For example, chimeric antibodies can be constructed as disclosed, for example, in WO 93/03151. Binding proteins which are derived from immunoglobulins and which are multivalent and multispecific, such as the “diabodies” described in WO 94/13804, can also be prepared.

[0143] Antibodies of the invention can be purified by methods well known in the art. For example, antibodies can be affinity purified by passing the antibodies over a column to which a protein, polypeptide, biologically active variant, or fusion protein of the invention is bound. The bound antibodies can then be eluted from the column, using a buffer with a high salt concentration.

[0144] Specific-binding polypeptides other than antibodies can also be generated. Specific-binding polypeptides are polypeptides which bind with a secreted protein or its variants and which have a measurably higher binding affinity for that protein and polypeptide fragments or variants of the protein than for other polypeptides tested for binding. Higher affinity by a factor of 10 is preferred, more preferably a factor of 100. Such polypeptides can be found, for example, using the yeast two-hybrid system.

[0145] Polynucleotides and proteins of the present invention exhibit one or more of the utilities or biological activities which are identified below. Biological activities and utilities of proteins of the invention can be provided by administration or use of the proteins themselves or by administration or use of polynucleotides encoding the proteins.

[0146] A protein of the invention can exhibit cytokine, cell proliferation (either inducing or inhibiting), or cell differentiation (either inducing or inhibiting) activity, or can induce production of other cytokines in certain cell populations. Many protein factors discovered to date, including all known cytokines, have exhibited activity in one or more factor-dependent cell proliferation assays; hence, the assays serve as a convenient confirmation of cytokine activity. The activity of a protein of the invention can be evidenced by any one of a number of routine factor-dependent cell proliferation assays for cell lines including, 32D (a mouse IL-3-dependent lymphoblast cell line, ATCC No. CRL-11346), DA2, DA1G, T10 (a human myeloma cell line, ATCC No. CRL-9068), B9, B9/11, BaF3, MC9/G, M+(preB M+), 2E8 (a mouse IL-7-dependent lymphoblast cell line, ATCC No. TIB-239), RB5, DA1, 123, T1165, HT2 (a mouse lymphoma cell line, ATCC No. CRL-8629), CTLL2, TF-1 (a human IL-5-unresponsive lymphoblast cell line, ATCC No. CRL-2003), Mo7e, and CMK.

[0147] Assays for T-cell or thymocyte proliferation include those described in CURRENT PROTOCOLS IN IMMUNOLOGY, Coligan et al., eds., Greene Publishing Associates and Wiley-Interscience (particularly chapter 3, In Vitro Assays for Mouse Lymphocyte Function 3.1-3.19; and chapter 7, Immunologic Studies in Humans); Takai et al., J. Immunol. 137:3494-3500, 1986; Bertagnolli et al., J. Immunol. 145:1706-1712, 1990; Bertagnolli et al., Cellular Immunology 133:327-341, 1991; Bertagnolli, et al., J. Immunol 149:3778-3783, 1992; and Bowman et al., J. Immunol. 152:1756-1761, 1994.

[0148] Assays for cytokine production and/or proliferation of spleen cells, lymph node cells, or thymocytes include those described in Kruisbeek and Shevach, Polyclonal T Cell Stimulation, in CURRENT PROTOCOLS IN IMMUNOLOGY, vol. 1, pp. 3.12.1-3.12.14, and Schreiber, Measurement of Mouse and Human Interleukin Gamma, in CURRENT PROTOCOLS IN IMMUNOLOGY, vol.1, pp. 6.8.1-6.8.8.

[0149] Assays for proliferation and differentiation of hematopoietic and lymphopoietic cells include those described in Bottomly, Measurement of Human and Murine Interleukin 2 and Interleukin 4, in CURRENT PROTOCOLS IN IMMUNOLOGY, vol. 1, pp. 6.3.1-6.3.12; deVries et al., J. Exp. Med. 173:1205-1211, 1991; Moreau et al., Nature 336:690-692, 1988; Greenberger et al., Proc. Natl. Acad. Sci. U.S.A. 80:2931-2938, 1983; Nordan, R., Measurement of mouse and human interleukin 6, in CURRENT PROTOCOLS EN IMMUNOLOGY, vol. 1, pp. 6.6.1-6.6.5; Smith et al., Proc. Natl. Acad. Sci. U.S.A. 83:1857-1861, 1986; Bennett et al., Measurement of Human Interleukin 11, in CURRENT PROTOCOLS IN IMMUNOLOGY, vol. 1, pp. 6.15.1; Ciarletta et al., Measurement of mouse and human Interleukin 9, in CURRENT PROTOCOLS IN IMMUNOLOGY, vol. 1, p.6.13.1.

[0150] Assays for T cell clone responses to antigens (which will identify, among others, proteins that affect APC-T cell interactions as well as direct T cell effects by measuring proliferation and cytokine production) include those described in CURRENT PROTOCOLS IN IMMUNOLOGY, especially chapters 3 (In Vitro Assays for Mouse Lymphocyte Function), chapter 6 (Cytokines and Their Cellular Receptors), and chapter 7 (Immunologic Studies in Humans); Weinberger et al., Proc. Natl. Acad. Sci. USA 77:6091-6095, 1980; Weinberger et al., Eur. J. Immun. 11:405-411, 1981; Takai et al., J. Immunol. 137:3494-3500, 1986; and Takai et al., J. Immunol. 140:508-512, 1988.

[0151] A protein of the present invention can be useful to support colony forming cells or factor-dependent cell lines, to regulate hematopoiesis, and to treat myeloid or lymphoid cell deficiencies. Such proteins can be used, either alone or in combination with other cytokines, to support the growth and proliferation of erythroid progenitor cells. The proteins can also be used to treat various anemias, in conjunction with irradiation or chemotherapy to stimulate the production of erythroid precursors or erythroid cells.

[0152] A protein of the invention can have CSF activity and can be used to support the growth and proliferation of myeloid cells, such as granulocytes, monocytes, or macrophages. Proteins with such activity can be used, for example, in conjunction with chemotherapy to prevent or treat myelo-suppression. Proteins of the invention can also be used to support the growth and proliferation of megakaryocytes and platelets, thereby allowing prevention-or treatment of platelet disorders such as thrombocytopenia. Proteins with such activity can be used to support the growth and proliferation of hematopoietic stem cells, either in place of or in conjunction with platelet transfusions. Proteins of the invention can be used to treat stem cell disorders, such as aplastic anemia and paroxysmal nocturnal hemoglobinuria, or to repopulate the stem cell compartment after irradiation or chemotherapy, either in-vivo or ex-vivo. For example, a protein of the invention can be used in conjunction with homologous or heterologous bone marrow transplantation or peripheral progenitor cell transplantation.

[0153] Suitable assays for proliferation and differentiation of various hematopoietic lines are cited above. Assays for embryonic stem cell differentiation which can identify proteins which influence embryonic hematopoiesis include those described in Johansson et al. Cellular Biology 15:141-151, 1995; Keller et al., Molecular and Cellular Biology 13:473-486, 1993; and McClanahan et al., Blood 81:2903-2915, 1993.

[0154] Assays for stem cell survival and differentiation include those described in Freshney, Methylcellulose colony forming assays, in CULTURE OF HEMATOPOIETIC CELLS, Freshney et al. eds., pp. 265-268, Wiley-Liss, Inc., New York, N.Y. 1994; Hirayama et al., Proc. Natl. Acad. Sci. USA 89:5907-5911, 1992; McNiece and Briddell, Primitive hematopoietic colony forming cells with high proliferative potential, in CULTURE OF HEMATOPOIETIC CELLS, pp. 23-39; Neben et al., Experimental Hematology 22:353-359, 1994; Ploemacher, Cobblestone area forming cell assay, in CULTURE OF HEMATOPOIETIC CELLS, pp. 1-21; Spooncer et al., Long term bone marrow cultures in the presence of stromal cells, in CULTURE OF HEMATOPOIETIC CELLS, pp. 163-179; Sutherland, Long term culture initiating cell assay, in CULTURE OF HEMATOPOIETIC CELLS, pp. 139-162. Such assays can be used to identify proteins which regulate lympho-hematopoiesis.

[0155] Compositions of the invention relate to isolated (purified) polypeptides and polynucleotides. These compositions are substantially free of other human proteins or human polynucleotides. A composition containing A is “substantially free of” B when at least 85% by weight of the total A+B in the composition is A. Preferably, A comprises at least about 90% by weight of the total of A+B in the composition, more preferably at least about 96% or even 99% by weight.

[0156] A protein of the invention also can have utility in compositions used for growth or differentiation of bone, cartilage, tendon, ligament, or nerve tissue, as well as for wound healing and tissue repair and replacement, and in the treatment of burns, incisions, and ulcers.

[0157] Proteins of the present invention can induce cartilage and/or bone growth in circumstances where bone is not normally formed and thus have an application in healing bone fractures and cartilage damage or defects in humans and other animals. A preparation employing a protein of the invention can have prophylactic use in closed as well as open fracture reduction and also in the improved fixation of artificial joints. De novo bone formation induced by an osteogenic agent contributes to the repair of congenital, trauma- or surgery-induced craniofacial defects and also is useful in cosmetic plastic surgery.

[0158] A protein of this invention can also be used in the treatment of periodontal disease and in other tooth repair processes. Such agents can provide an environment to attract bone-forming cells, stimulate growth of bone-forming cells, or induce differentiation of progenitors of bone-forming cells. A protein of the invention can be used to treat osteoporosis or osteoarthritis, for example, through stimulation of bone and/or cartilage repair or by blocking inflammation. Mechanisms of destroying tissue mediated by inflammatory processes, such as collagenase or osteoclast activity, can also be inhibited.

[0159] Tendon or ligament formation can also be influenced by a protein of the invention. A protein of the invention which induces tendon/ligament-like tissue or other tissue formation in circumstances where such tissue is not normally formed can be used to heal tendon or ligament tears, deformities, and other tendon or ligament defects in humans and other animals. A preparation employing a tendon/ligament-like tissue inducing protein can be used to prevent damage to tendon or ligament tissue, as well as in the improved fixation of tendon or ligament to bone or other tissues, and to repair defects to tendon or ligament tissue. De novo tendon/ligament-like tissue formation induced by a composition of the invention contributes to the repair of congenital, trauma-induced, or other tendon or ligament defects of other origin and can also be used in cosmetic plastic surgery, for attachment or repair of tendons or ligaments.

[0160] Compositions of the invention can provide an environment which will attract tendon- or ligament-forming cells, stimulate growth of tendon- or ligament-forming cells, induce differentiation of progenitors of tendon- or ligament-forming cells, or induce growth of tendon/ligament cells or progenitors ex vivo. Such cells can then be returned to the body to effect tissue repair. Compositions of the invention can also be used to treat tendinitis, carpal tunnel syndrome, and other tendon or ligament defects. Such compositions can optionally include an appropriate matrix and/or sequestering agent as a pharmaceutically acceptable carrier, as is well known in the art.

[0161] A protein of the invention can also be useful for proliferation of neural cells and for regeneration of nerve and brain tissue, i.e. for the treatment of central and peripheral nervous system diseases and neuropathies, as well as mechanical and traumatic disorders. More specifically, a protein can be used in the treatment of diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Shy-Drager syndrome. Other conditions which can be treated in accordance with the invention include mechanical and traumatic disorders, such as spinal cord disorders and head trauma, and cerebrovascular diseases, such as stroke. Peripheral neuropathies resulting from chemotherapy or other medical therapies can be treated using a protein of the invention.

[0162] Proteins of the invention can also be used to promote better or faster closure of non-healing wounds, including pressure ulcers, ulcers associated with vascular insufficiency, or surgical and traumatic wounds.

[0163] A protein of the invention can also affect generation or regeneration of other tissues, such as organs (including, for example, pancreas, liver, intestine, kidney, skin, endothelium), muscle (smooth, skeletal, or cardiac), and vascular (including vascular endothelium) tissue, or for promoting the growth of cells of which such tissues are comprised. Part of the desired effects can be by inhibition or modulation of fibrotic scarring to allow normal tissue to regenerate. A protein of the invention can also exhibit angiogenic activity.

[0164] A protein of the present invention can be useful for gut protection or regeneration, and for treatment of lung or liver fibrosis, reperfusion injury in various tissues, and conditions resulting from systemic cytokine damage. A protein of the invention can also be useful for promoting or inhibiting differentiation of tissues described above from precursor tissues or cells or for inhibiting the growth of tissues described above.

[0165] Assays for tissue generation activity include those described for bone, cartilage, and tendon in WO 95/16035, for neuronal tissue in WO 95/05846, and for skin and endothelial tissue in WO 91/07491. Assays for wound healing activity include, for example, those described in Winter, EPIDERMAL WOUND HEALING, polypeptides 71-112 (Maibach and Rovee, eds.), Year Book Medical Publishers, Inc., Chicago, and Eaglstein and Mertz, J. Invest. Dermatol 71:382-84 (1978).

[0166] A protein of the present invention can also demonstrate activity as a receptor, receptor ligand, or inhibitor or agonist of a receptor/ligand interaction. Examples of such receptors and ligands include cytokine receptors and their ligands, receptor kinases and their ligands, receptor phosphatases and their ligands, receptors involved in cell-cell interactions and their ligands, including cellular adhesion molecules such as selectins, integrins, and their ligands, and receptor/ligand pairs involved in antigen presentation, antigen recognition and development of cellular and humoral immune responses. Receptors and ligands are also useful for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction. A protein of the invention, including fragments of receptors and ligands, can itself be useful as an inhibitor of receptor/ligand interactions.

[0167] Suitable assays for receptor-ligand activity include those described in CURRENT PROTOCOLS IN IMMUNOLOGY, chapter 7.28, Measurement of Cellular Adhesion under static conditions, pages 7.28.1-7.28.22, Takai et al., Proc. Natl. Acad. Sci. USA 84:6864-6868, 1987; Bierer et al., J. Exp. Med. 168:1145-1156, 1988; Rosenstein et al., J. Exp. Med. 169:149-160 1989; Stoltenborg et al., J. Immunol. Methods 175:59-68, 1994; Stitt et al., Cell 80:661-670, 1995.

[0168] A protein of the invention can be used in a pharmaceutical composition. Compositions comprising proteins or polynucleotides of the invention have therapeutic applications, both for human patients and veterinary patients, such as domestic animals and thoroughbred horses. Such compositions can optionally include a pharmaceutically acceptable carrier. In addition to protein and carrier, such a composition can also contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. Characteristics of a carrier will depend on the route of administration. Compositions of the invention can also contain cytokines, lymphokines, or other hematopoietic factors such as M-CSF, GM-CSF, TNF, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-i11, IL-12, IL-13, IL-14, IL-15, IFN, TNF0, TNF1, TNF2, G-CSF, Meg-CSF, thrombopoietin, stem cell factor, erythropoietin, or growth factors such as epidermal growth factor (EGF), platelet derived growth factor (PDGF), transforming growth factors (TGF-α and TGF-β), or insulin-like growth factor (IGF).

[0169] A pharmaceutical composition can also contain other agents which either enhance the activity of the protein or complement its activity or use in treatment. Such additional factors and/or agents can be included in the pharmaceutical composition to produce a synergistic effect with a protein of the invention or to minimize side effects. Conversely, a protein of the invention can be included in formulations of a particular factor, such as a cytokine, lymphokine, other hematopoietic factor, thrombolytic or anti-thrombotic factor, or anti-inflammatory agent to minimize side effects of the factor.

[0170] A protein of the present invention can be active in multimers (e.g., heterodimers or homodimers) or complexes with itself or other proteins, and compositions of the invention can comprise a protein of the invention in such a multimeric or complexed form. For example, a composition of the invention can be in the form of a complex of a protein or proteins of the invention together with protein or peptide antigens. The protein or peptide antigen will deliver a stimulatory signal to both B and T lymphocytes. B lymphocytes will respond to antigen through their surface immunoglobulin receptor. T lymphocytes will respond to antigen through the T cell receptor (TCR) following presentation of the antigen by MHC proteins. MHC proteins and structurally related proteins, including those encoded by class I and class II MHC genes on host cells, can present the peptide antigen(s) to T lymphocytes. Antigen components can also be supplied as purified MHC-peptide complexes alone or with co-stimulatory molecules which can directly signal T cells. Alternatively, antibodies able to bind surface immunoglobulin and other molecules on B cells, as well as antibodies able to bind the TCR and other molecules on T cells, can be combined with a composition of the invention.

[0171] A composition of the invention can be in the form of a liposome in which a protein of the invention is combined, in addition to other pharmaceutically acceptable carriers, with amphipathic agents such as lipids, which exist in aggregated form as micelles, insoluble monolayers, liquid crystals, or lamellar layers in aqueous solution. Suitable lipids for liposomal formulation include monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acids, and the like. Preparation of liposomal formulations is within the level of skill in the art, as disclosed, for example, in U.S. Pat. Nos. 4,235,871, 4,501,728, 4,837,028, and 4,737,323.

[0172] A therapeutically effective amount of a protein of the invention is administered to a mammal having a condition to be treated. The amount of protein which is therapeutically effective is that amount of protein which is sufficient to treat, heal, prevent, or ameliorate the condition, or to increase the rate of such treatment. Proteins of the invention can be administered either alone or in combination with other therapeutic agents, such as cytokines, lymphokines, or other hematopoietic factors. Other therapeutic agents can be administered simultaneously or sequentially with proteins of the invention, as determined by the attending physician.

[0173] Compositions of the invention can be inhaled, ingested, applied topically, or administered by cutaneous, subcutaneous, intraperitoneal, parenteral or intravenous injection. When a therapeutically effective amount of protein of the present invention is administered orally, protein of the present invention will be in the form of a tablet, capsule, powder, solution or elixir. When administered in tablet form, the pharmaceutical composition of the invention can additionally contain a solid carrier such as a gelatin or an adjuvant. The tablet, capsule, and powder contain from about 5-95%, 25-90%, 30-80%, 40-75%, or 50% protein of the invention by weight. When administered in liquid form, a liquid carrier such as water, petroleum, oils of animal or plant origin such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils can be added. The liquid form of the composition can further contain physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol, or polyethylene glycol. When administered in liquid form, the pharmaceutical composition contains from about 0.5-90%, 1-80%,5-75%,10-65%, 20-50%, 10-50%, or 25-40% by weight of protein of the invention.

[0174] When a therapeutically effective amount of protein of the present invention is administered by intravenous, cutaneous, or subcutaneous injection, a pyrogen-free, parenterally acceptable aqueous solution of the protein is preferred. The skilled artisan can readily prepare an acceptable protein solution with suitable pH, isotonicity, and stability. A solution of the composition for intravenous, cutaneous, or subcutaneous injection should also contain an isotonic vehicle, such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer's Injection, or other vehicle as known in the art. Stabilizers, preservatives, buffers, antioxidants, or other additives known to those of skill in the art can also be added to the composition.

[0175] The amount of protein of the present invention in the pharmaceutical composition of the present invention will depend upon the nature and severity of the condition being treated and on the nature of prior treatments which the patient has undergone. Ultimately, the attending physician will decide the amount of protein of the present invention with which to treat each individual patient. Initially, the attending physician will administer low doses of protein of the present invention and observe the patient's response. Larger doses of protein of the present invention can be administered until the optimal therapeutic effect is obtained for the patient, and at that point the dosage is not increased further. It is contemplated that the various pharmaceutical compositions used to practice the method of the present invention should contain about 0.01 μg to about 100 mg (preferably about 0.1 μg to about 10 mg, more preferably about 0.1 μg to about 1 mg) of protein of the present invention per kg body weight.

[0176] Duration of intravenous therapy using a composition of the invention will vary, depending on the severity of the disease being treated and the condition and potential idiosyncratic response of each individual patient. It is contemplated that the duration of each application of a composition of the invention will be in the range of 12 to 24 hours of continuous intravenous administration. Ultimately, the attending physician will decide on the appropriate duration of intravenous therapy.

[0177] A composition of the invention which is useful for bone, cartilage, tendon or ligament regeneration can be administered topically, systematically, or locally in an implant or device. Encapsulation or injection in a viscous form for delivery to the site of bone, cartilage or tissue damage is also possible. Topical administration can be suitable for wound healing and tissue repair. Optionally, therapeutic agents other than a protein of the invention can be included in the composition, as described above.

[0178] To affect bone or cartilage formation, a composition of the invention would include a matrix capable of delivering the composition to the site of bone or cartilage damage and for providing a structure for the developing bone and cartilage. Optimally, the matrix would be capable of resorption into the body. Matrices can be formed of materials presently in use for other implanted medical applications, the choice of material being based on biocompatibility, biodegradability, mechanical properties, cosmetic appearance, and interface properties. Suitable biodegradable matrix materials include chemically defined calcium sulfate, tricalciumphosphate, hydroxyapatite, polylactic acid, polyglycolic acid, polyanhydride, bone or dermal collagen, pure proteins, and extracellular matrix components. Suitable nonbiodegradable and chemically defined matrix materials include sintered hydroxyapatite, bioglass, aluminates, or other ceramics. Individual matrix components can be modified, for example, to affect pore size, particle size, particle shape, and biodegradability. Combinations of materials can be used, as is known in the art.

[0179] Sequestering agents, such as carboxymethyl cellulose or an autologous blood clot, can be employed to prevent protein compositions from dissociating from the matrix. Sequestering agents include cellulosic materials such as alkylcelluloses (including hydroxyalkylcelluloses), including methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl-methylcellulose, and carboxymethylcellulose, the most preferred being cationic salts of carboxymethylcellulose (CMC). Other preferred sequestering agents include hyaluronic acid, sodium alginate, polyethylene glycol, polyoxyethylene oxide, carboxyvinyl polymer and polyvinyl alcohol. The amount of sequestering agent is based on total formulation weight, such as 0.5-20% or 1-10%, and should be an amount of sequestering agent which prevents desorbtion of the protein from the polymer matrix but which permits progenitor cells to infiltrate the matrix, so that the protein can assist the osteogenic activity of the progenitor cells.

[0180] The dosage regimen of a protein-containing pharmaceutical composition to be used in tissue regeneration will be determined by the attending physician considering various factors which modify the action of the proteins, e.g., amount of tissue weight desired to be formed, the site of damage, the condition of the damaged tissue, the size of a wound, type of damaged tissue (e.g., bone), the patient's age, sex, and diet, the severity of any infection, time of administration, and other clinical factors. The dosage can vary with the type of matrix used in the reconstitution and whether other therapeutic agents, such as growth factors, are included. Progress of the treatment can be monitored by periodic assessment of tissue/bone growth and/or repair, for example, using X-rays, histomorphometric determinations, or tetracycline labeling.

[0181] Polynucleotides of the invention can also be used for gene therapy. Polynucleotides can be introduced either in vivo or ex vivo into cells for expression in a mammalian subject. Cells can be cultured ex vivo in the presence of proteins of the invention in order to produce a desired effect on or activity in such cells. Treated cells can then be introduced in vivo for therapeutic purposes, as is known in the art. Polynucleotides of the invention can be administered by known methods of introducing polynucleotides into a cell or organism (including in the form of viral vectors or naked DNA).

[0182] Polynucleotides of the invention can also be delivered to subjects for the purpose of screening test compounds for those which are useful for enhancing transfer of polynucleotides of the invention to a cell or for enhancing subsequent biological effects of the polynucleotides within the cell. Such biological effects include hybridization to complementary mRNA and inhibition of its translation, expression of the polynucleotide to form mRNA and/or protein, and replication and integration of the polynucleotide.

[0183] Test compounds which can be screened include any substances, whether natural products or synthetic, which can be administered to the subject. Libraries or mixtures of compounds can be tested. The compounds or substances can be those for which a pharmaceutical effect is previously known or unknown. The compounds or substances can be delivered before, after, or concomitantly with the polynucleotides. They can be administered separately or in admixture with the polynucleotides.

[0184] Integration of delivered polynucleotides can be monitored by any means known in the art. For example, Southern blotting of the delivered polynucleotides can be performed. A change in the size of the fragments of the delivered polynucleotides indicates integration. Replication of the delivered polynucleotides can be monitored inter alia by detecting incorporation of labeled nucleotides combined with hybridization to a specific nucleotide probe. Expression of a polynucleotide of the invention can be monitored by detecting production of mRNA which hybridizes to the delivered polynucleotide or by detecting protein. Proteins of the invention can be detected immunologically. Thus, delivery of polynucleotides of the invention according to the present invention provides an excellent system for screening test compounds for their ability to enhance delivery, integration, hybridization, expression, replication or integration in an animal, preferably a mammal, more preferably a human.

[0185] Polynucleotides of the invention can be used for a variety of research purposes. Any or all of these research utilities are capable of being developed into reagent grade or kit format for commercialization as research products. For example, polynucleotides can be used to express recombinant protein for analysis, characterization, or therapeutic use. Polynucleotides can also be used as markers for tissues in which the corresponding protein is preferentially expressed, either constitutively or at a particular stage of tissue differentiation or development or in disease states. Polynucleotides can also be used as molecular weight markers on Southern gels or, when labeled, for example, with a fluorescent tag or a radiolabel, polynucleotides can be used as chromosome markers, to identify chromosomes for gene mapping. Potential genetic disorders can be identified by comparing the sequences of wild-type polynucleotides of the invention with endogenous nucleotide sequences in patients. Polynucleotides of the invention can also be used as probes for the discovery of novel, related DNA sequences, to derive PCR primers for genetic fingerprinting, as probes to “subtract-out” known sequences in the process of discovering other novel polynucleotides, for selecting and making oligomers for attachment to a gene chip or other support, to raise anti-protein antibodies using DNA immunization techniques, and as antigens, to raise anti-DNA antibodies or to elicit another immune response.

[0186] Where the polynucleotide encodes a protein which binds or potentially binds to another protein, such as in a receptor-ligand interaction, the polynucleotide can also be used in interaction trap assays, such as the yeast two-hybrid assay, to identify polynucleotides encoding the protein with which binding occurs or to identify inhibitors of the binding interaction, for example in drug screening assays.

[0187] Proteins of the invention can similarly be used in assays to determine biological activity, including use in a panel of multiple proteins for high-throughput screening, to raise antibodies or to elicit another immune response, as a reagent in assays designed to quantitatively determine levels of the protein (or its receptor) in biological fluids, as markers for tissues in which the protein is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in a disease state), and to identify related receptors or ligands. Where the protein binds or potentially binds to another protein such as, for example, in a receptor-ligand interaction, the protein can be used to identify the other protein with which binding occurs or to identify inhibitors of the binding interaction. Proteins involved in these binding interactions can also be used to screen for peptide or small molecule inhibitors or agonists of the binding interaction.

[0188] Polynucleotides of the invention can also be used on polynucleotide arrays. Polynucleotide arrays provide a high throughput technique that can assay a large number of polynucleotide sequences in a sample. This technology can be used as a diagnostic tool and as a tool to test for differential expression of genes having the coding sequences disclosed herein.

[0189] To create arrays, single-stranded polynucleotide probes can be spotted onto a substrate in a two-dimensional matrix or array. The single-stranded polynucleotide probes can comprise at least 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or 30 or more contiguous nucleotides selected from the nucleotide sequences shown in SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, or 43. The substrate can be any substrate to which polynucleotide probes can be attached, including but not limited to glass, nitrocellulose, silicon, and nylon. Polynucleotide probes can be bound to the substrate by either covalent bonds or by non-specific interactions, such as hydrophobic interactions. Techniques for constructing arrays and methods of using these arrays are described in EP No. 0 799 897; PCT No. WO 97/29212; PCT No. WO 97/27317; EP No. 0 785 280; PCT No. WO 97/02357; U.S. Pat. No. 5,593,839; U.S. Pat. No. 5,578,832; EP No. 0 728 520; U.S. Pat. No. 5,599,695; EP No. 0 721 016; U.S. Pat. No. 5,556,752; PCT No. WO 95/22058; and U.S. Pat. No. 5,631,734. Commercially available polynucleotide arrays, such as Affymetrix GeneChip™, can also be used. Use of the GeneChip™ to detect gene expression is described, for example, in Lockhart et al., Nature Biotechnology 14:1675 (1996); Chee et al., Science 274:610 (1996); Hacia et al., Nature Genetics 14:441, 1996; and Kozal et al., Nature Medicine 2:753, 1996.

[0190] Biological samples comprising single-stranded polynucleotides can be labeled and then hybridized to the probes. Detectable labels which can be used include but are not limited to radiolabels, biotinylated labels, fluorophors, and chemiluminescent labels. Double stranded polynucleotides, comprising the labeled sample polynucleotides bound to polynucleotide probes, can be detected once the unbound portion of the sample is washed away, Biological samples in which expression of genes comprising polynucleotides of the invention can be examined include samples of diseased and non-diseased tissues, samples of tissues suspected of being diseased (particularly tissues suspected of being neoplastic), samples of different cell types, samples of cells at different developmental stages, samples of tissues from different species, and the like.

[0191] The complete contents of all references cited in this disclosure are expressly incorporated herein by reference. While certain embodiments of the invention have been described with particularity herein, those of skill in the art will recognize that various modifications of the invention can be made. It is understood that such modifications and variations are included within the scope of the appended claims.

1 46 1 1325 DNA human 1 gttcacgttc gcggccttct gctacatgct ggcgctgctg ctcactgccg cgctcatctt 60 cttcgccatt tggcacatta tagcatttga tgagctgaag actgattaca agaatcctat 120 agaccagtgt aataccctga atccccttgt actcccagag tacctcatcc acgctttctt 180 ctgtgtcatg tttctttgtg cagcagagtg gcttacactg ggtctcaata tgcccctctt 240 ggcatatcat atttggaggt atatgagtag accagtgatg agtggcccag gactctatga 300 ccctacaacc atcatgaatg cagatattct agcatattgt cagaaggaag gatggtgcaa 360 attagctttt tatcttctag cattttttta ctacctatat ggcatgatct atgttttggt 420 gagctcttag aacaacacac agaagaattg gtccagttaa gtgcatgcaa aaagccacca 480 aatgaaggga ttctatccag caagatcctg tccaagagta gcctgtggaa tctgatcagt 540 tactttaaaa aatgactcct tattttttaa atgtttccac atttttgctt gtggaaagac 600 tgttttcata tgttatactc agataaagat tttaaatggt attacgtata aattaatata 660 aaatggttac ctctggtgtt gacaggtttg aacttgcact tcttaaggaa cagccataat 720 cctctgaatg atgcattaat tactgactgt cctagtacat tggaagcttt tgtttatagg 780 aacttgtagg gctcattttg gtttcattga aacagtatct aattataaat tagctgtaga 840 tatcaggtgc ttctgatgaa gtgaaaatgt atatctgact agtgggaaac ttcatgggtt 900 tcctcatctg tcatgtcgat gattatatat ggatacattt acaaaaataa aaagcgggaa 960 ttttcccttc gcttgaatat tatccctgta tattgcatga atgagagatt tcccatattt 1020 ccatcagagt aataaatata cttgctttaa ttcttaagca taagtaaaca tgatataaaa 1080 atatatgctg aattacttgt gaagaatgca tttaaagcta ttttaaatgt gtttttattt 1140 gtaagacatt acttattaag aaattggtta ttatgcttac tgttctaatc tggtggtaaa 1200 ggtattctta agaatttgca ggtactacag attttcaaaa ctgaatgaga gaaaattgta 1260 taaccatcct gctgttcctt tagtgcaata caataaaact ctgaaattaa gactcaaaaa 1320 aaaaa 1325 2 142 PRT human 2 Phe Thr Phe Ala Ala Phe Cys Tyr Met Leu Ala Leu Leu Leu Thr Ala 1 5 10 15 Ala Leu Ile Phe Phe Ala Ile Trp His Ile Ile Ala Phe Asp Glu Leu 20 25 30 Lys Thr Asp Tyr Lys Asn Pro Ile Asp Gln Cys Asn Thr Leu Asn Pro 35 40 45 Leu Val Leu Pro Glu Tyr Leu Ile His Ala Phe Phe Cys Val Met Phe 50 55 60 Leu Cys Ala Ala Glu Trp Leu Thr Leu Gly Leu Asn Met Pro Leu Leu 65 70 75 80 Ala Tyr His Ile Trp Arg Tyr Met Ser Arg Pro Val Met Ser Gly Pro 85 90 95 Gly Leu Tyr Asp Pro Thr Thr Ile Met Asn Ala Asp Ile Leu Ala Tyr 100 105 110 Cys Gln Lys Glu Gly Trp Cys Lys Leu Ala Phe Tyr Leu Leu Ala Phe 115 120 125 Phe Tyr Tyr Leu Tyr Gly Met Ile Tyr Val Leu Val Ser Ser 130 135 140 3 1277 DNA human 3 cacgaggaaa cccacgaggg gacgcggccg aggagggtcg ctgtccaccc gggggcgtgg 60 gagtgaggta ccagattcag cccatttggc cccgacgcct ctgttctcgg aatccgggtg 120 ctgcggattg aggtcccggt tcctaacggt gggatcggtg tcctcgggat gagatttggc 180 gtttcctcgg ggctttggtg ggatcggtgt cctcaggatg agatttaggg tttcctcggg 240 gctttcggga tcttcaccta atatccggta ttattttatg agaggagtgg tcttggctgt 300 cagaactgga tccctggggt gatatttggg aattagtgga gtgatctctg aagacctagg 360 gctatgatct ggagctgctg tggctgaaat ttggggcctc tgaagtggca tggagattga 420 ggtccagaga gcctgagatc ttgagggctg acatttggag agatggggtc gagggttgtc 480 tttgggcctt gactgctttg ggcctttctc actctcattc ccgggatgct ttgccagaat 540 ctctgctgga ttggccgtaa ccctgtcccc gagcgggctc acagggtctg aaggccacgc 600 atgaggcaaa ggtaaagttc tgagccaccc ggtgcctcct tcccaggact gcaagatgga 660 ggaaggcggg aacctaggag gcctgattaa gatggtccat ctactggtct tgtcaggtgc 720 ctggggcatg caaatgtggg tgaccttcgt ctcaggcttc ctgcttttcc gaagccttcc 780 ccgacatacc ttcggactag tgcagagcaa actcttcccc ttctacttcc acatctccat 840 gggctgtgcc ttcatcaacc tctgcatctt ggcttcacag catgcttggg ctcagctcac 900 attctgggag gccagccagc tttacctgct gttcctgagc cttacgctgg ccactgtcaa 960 cgcccgctgg ctggaacccc gcaccacagc tgccatgtgg gccctgcaaa ccgtggagaa 1020 ggagcgaggc ctgggtgggg aggtaccagg cagccaccag ggtcccgatc cctaccgcca 1080 gctgcgagag aaggacccca agtacagtgc tctccgccag aatttcttcc gctaccatgg 1140 gctgtcctct ctttgcaatc tgggctgcgt cctgagcaat gggctctgtc tcgctggcct 1200 tgccctggaa ataaggagcc tctagcatgg gccctgcatg ctaataaatg cttcttcaga 1260 aaaaaaaaaa aaaaaaa 1277 4 189 PRT human 4 Met Glu Glu Gly Gly Asn Leu Gly Gly Leu Ile Lys Met Val His Leu 1 5 10 15 Leu Val Leu Ser Gly Ala Trp Gly Met Gln Met Trp Val Thr Phe Val 20 25 30 Ser Gly Phe Leu Leu Phe Arg Ser Leu Pro Arg His Thr Phe Gly Leu 35 40 45 Val Gln Ser Lys Leu Phe Pro Phe Tyr Phe His Ile Ser Met Gly Cys 50 55 60 Ala Phe Ile Asn Leu Cys Ile Leu Ala Ser Gln His Ala Trp Ala Gln 65 70 75 80 Leu Thr Phe Trp Glu Ala Ser Gln Leu Tyr Leu Leu Phe Leu Ser Leu 85 90 95 Thr Leu Ala Thr Val Asn Ala Arg Trp Leu Glu Pro Arg Thr Thr Ala 100 105 110 Ala Met Trp Ala Leu Gln Thr Val Glu Lys Glu Arg Gly Leu Gly Gly 115 120 125 Glu Val Pro Gly Ser His Gln Gly Pro Asp Pro Tyr Arg Gln Leu Arg 130 135 140 Glu Lys Asp Pro Lys Tyr Ser Ala Leu Arg Gln Asn Phe Phe Arg Tyr 145 150 155 160 His Gly Leu Ser Ser Leu Cys Asn Leu Gly Cys Val Leu Ser Asn Gly 165 170 175 Leu Cys Leu Ala Gly Leu Ala Leu Glu Ile Arg Ser Leu 180 185 5 1610 DNA human 5 cacagtaggt ccctcggctc agtcggccca gcccctctca gtcctcccca acccccacaa 60 ccgcccgcgg ctctgagacg cggccccggc ggcggcggca gcagctgcag catcatctcc 120 accctccagc catggaagac ctggaccagt ctcctctggt ctcgtcctcg gacagcccac 180 cccggccgca gcccgcgttc aagtaccagt tcgtgaggga gcccgaggac gaggaggaag 240 aagaggagga ggaagaggag gacgaggacg aagacctgga ggagctggag gtgctggaga 300 ggaagcccgc cgccgggctg tccgcggccc cagtgcccac cgcccctgcc gccggcgcgc 360 ccctgatgga cttcggaaat gacttcgtgc cgccggcgcc ccggggaccc ctgccggccg 420 ctccccccgt cgccccggag cggcagccgt cttgggaccc gagcccggtg tcgtcgaccg 480 tgcccgcgcc atccccgctg tctgctgccg cagtctcgcc ctccaagctc cctgaggacg 540 acgagcctcc ggcccggcct ccccctcctc ccccggccag cgtgagcccc caggcagagc 600 ccgtgtggac cccgccagcc ccggctcccg ccgcgccccc ctccaccccg gccgcgccca 660 agcgcagggg ctcctcgggc tcagtggttg ttgacctcct gtactggaga gacattaaga 720 agactggagt ggtgtttggt gccagcctat tcctgctgct ttcattgaca gtattcagca 780 ttgtgagcgt aacagcctac attgccttgg ccctgctctc tgtgaccatc agctttagga 840 tatacaaggg tgtgatccaa gctatccaga aatcagatga aggccaccca ttcagggcat 900 atctggaatc tgaagttgct atatctgagg agttggttca gaagtacagt aattctgctc 960 ttggtcatgt caactgcacg ataaaggaac tcaggcgcct cttcttagtt gatgatttag 1020 ttgattctct gaagtttgca gtgttgatgt gggtatttac ctatgttggt gccttgttta 1080 atggtctgac actactgatt ttggctctca tttcactctt cagtgttcct gttatttatg 1140 aacggcatca ggcacagata gatcattatc taggacttgc aaataagaat gttaaagatg 1200 ctatggctaa aatccaagca aaaatccctg gattgaagcg caaagctgaa tgaaaacgcc 1260 caaaataatt agtaggagtt catctttaaa ggggatattc atttgattat acgggggagg 1320 gtcagggaag aacgaacctt gacgttgcag tgcagtttca cagatcgttg ttagatcttt 1380 atttttagcc atgcactgtt gtgaggaaaa attacctgtc ttgactgcca tgtgttcatc 1440 atcttaagta ttgtaagctg ctatgtatgg atttaaaccg taatcatatc tttttcctat 1500 ctgaggcact ggtggaataa aaaacctgta tattttactt tgttgcagat agtcttgccg 1560 catcttggca agttgcagag atggtggagc tagaaaaaaa aaaaaaaaaa 1610 6 373 PRT human 6 Met Glu Asp Leu Asp Gln Ser Pro Leu Val Ser Ser Ser Asp Ser Pro 1 5 10 15 Pro Arg Pro Gln Pro Ala Phe Lys Tyr Gln Phe Val Arg Glu Pro Glu 20 25 30 Asp Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Asp Glu Asp Glu Asp 35 40 45 Leu Glu Glu Leu Glu Val Leu Glu Arg Lys Pro Ala Ala Gly Leu Ser 50 55 60 Ala Ala Pro Val Pro Thr Ala Pro Ala Ala Gly Ala Pro Leu Met Asp 65 70 75 80 Phe Gly Asn Asp Phe Val Pro Pro Ala Pro Arg Gly Pro Leu Pro Ala 85 90 95 Ala Pro Pro Val Ala Pro Glu Arg Gln Pro Ser Trp Asp Pro Ser Pro 100 105 110 Val Ser Ser Thr Val Pro Ala Pro Ser Pro Leu Ser Ala Ala Ala Val 115 120 125 Ser Pro Ser Lys Leu Pro Glu Asp Asp Glu Pro Pro Ala Arg Pro Pro 130 135 140 Pro Pro Pro Pro Ala Ser Val Ser Pro Gln Ala Glu Pro Val Trp Thr 145 150 155 160 Pro Pro Ala Pro Ala Pro Ala Ala Pro Pro Ser Thr Pro Ala Ala Pro 165 170 175 Lys Arg Arg Gly Ser Ser Gly Ser Val Val Val Asp Leu Leu Tyr Trp 180 185 190 Arg Asp Ile Lys Lys Thr Gly Val Val Phe Gly Ala Ser Leu Phe Leu 195 200 205 Leu Leu Ser Leu Thr Val Phe Ser Ile Val Ser Val Thr Ala Tyr Ile 210 215 220 Ala Leu Ala Leu Leu Ser Val Thr Ile Ser Phe Arg Ile Tyr Lys Gly 225 230 235 240 Val Ile Gln Ala Ile Gln Lys Ser Asp Glu Gly His Pro Phe Arg Ala 245 250 255 Tyr Leu Glu Ser Glu Val Ala Ile Ser Glu Glu Leu Val Gln Lys Tyr 260 265 270 Ser Asn Ser Ala Leu Gly His Val Asn Cys Thr Ile Lys Glu Leu Arg 275 280 285 Arg Leu Phe Leu Val Asp Asp Leu Val Asp Ser Leu Lys Phe Ala Val 290 295 300 Leu Met Trp Val Phe Thr Tyr Val Gly Ala Leu Phe Asn Gly Leu Thr 305 310 315 320 Leu Leu Ile Leu Ala Leu Ile Ser Leu Phe Ser Val Pro Val Ile Tyr 325 330 335 Glu Arg His Gln Ala Gln Ile Asp His Tyr Leu Gly Leu Ala Asn Lys 340 345 350 Asn Val Lys Asp Ala Met Ala Lys Ile Gln Ala Lys Ile Pro Gly Leu 355 360 365 Lys Arg Lys Ala Glu 370 7 1499 DNA human 7 gtcgagagga cgaggtgccg ctgcctggag aatcctccgc tgccgtcggc tcccggagcc 60 cagccctttc ctaacccaac ccaacctagc ccagtcccag ccgccagcgc ctgtccctgt 120 cacggacccc agcgttacca tgcatcctgc cgtcttccta tccttacccg acctcagatg 180 ctcccttctg ctcctggtaa cttgggtttt tactcctgta acaactgaaa taacaagtct 240 tgatacagag aatatagatg aaattttaaa caatgctgat gttgctttag taaattttta 300 tgctgactgg tgtcgtttca gtcagatgtt gcatccaatt tttgaggaag cttccgatgt 360 cattaaggaa gaatttccaa atgaaaatca agtagtgttt gccagagttg attgtgatca 420 gcactctgac atagcccaga gatacaggat aagcaaatac ccaaccctca aattgtttcg 480 taatgggatg atgatgaaga gagaatacag gggtcagcga tcagtgaaag cattggcaga 540 ttacatcagg caacaaaaaa gtgaccccat tcaagaaatt cgggacttag cagaaatcac 600 cactcttgat cgcagcaaaa gaaatatcat tggatatttt gagcaaaagg actcggacaa 660 ctatagagtt tttgaacgag tagcgaatat tttgcatgat gactgtgcct ttctttctgc 720 atttggggat gtttcaaaac cggaaagata tagtggcgac aacataatct acaaaccacc 780 agggcattct gctccggata tggtgtactt gggagctatg acaaattttg atgtgactta 840 caattggatt caagataaat gtgttcctct tgtccgagaa ataacatttg aaaatggaga 900 ggaattgaca gaagaaggac tgccttttct catactcttt cacatgaaag aagatacaga 960 aagtttagaa atattccaga atgaagtagc tcggcaatta ataagtgaaa aaggtacaat 1020 aaacttttta catgccgatt gtgacaaatt tagacatcct cttctgcaca tacagaaaac 1080 tccagcagat tgtcctgtaa tcgctattga cagctttagg catatgtatg tgtttggaga 1140 cttcaaagat gtattaattc ctggaaaact caagcaattc gtatttgact tacattctgg 1200 aaaactgcac agagaattcc atcatggacc tgacccaact gatacagccc caggagagca 1260 agcccaagat gtagcaagca gtccacctga gagctccttc cagaaactag cacccagtga 1320 atataggtat actctattga gggatcgaga tgagctttaa aaacttgaaa aacagtttgt 1380 aagcctttca acagcagcat caacctacgt ggtggaaata gtaaacctat attttcataa 1440 ttctatgtgt atttttattt tgaataaaca gaaagaaatt taaaaaaaaa aaaaaaaaa 1499 8 406 PRT human 8 Met His Pro Ala Val Phe Leu Ser Leu Pro Asp Leu Arg Cys Ser Leu 1 5 10 15 Leu Leu Leu Val Thr Trp Val Phe Thr Pro Val Thr Thr Glu Ile Thr 20 25 30 Ser Leu Asp Thr Glu Asn Ile Asp Glu Ile Leu Asn Asn Ala Asp Val 35 40 45 Ala Leu Val Asn Phe Tyr Ala Asp Trp Cys Arg Phe Ser Gln Met Leu 50 55 60 His Pro Ile Phe Glu Glu Ala Ser Asp Val Ile Lys Glu Glu Phe Pro 65 70 75 80 Asn Glu Asn Gln Val Val Phe Ala Arg Val Asp Cys Asp Gln His Ser 85 90 95 Asp Ile Ala Gln Arg Tyr Arg Ile Ser Lys Tyr Pro Thr Leu Lys Leu 100 105 110 Phe Arg Asn Gly Met Met Met Lys Arg Glu Tyr Arg Gly Gln Arg Ser 115 120 125 Val Lys Ala Leu Ala Asp Tyr Ile Arg Gln Gln Lys Ser Asp Pro Ile 130 135 140 Gln Glu Ile Arg Asp Leu Ala Glu Ile Thr Thr Leu Asp Arg Ser Lys 145 150 155 160 Arg Asn Ile Ile Gly Tyr Phe Glu Gln Lys Asp Ser Asp Asn Tyr Arg 165 170 175 Val Phe Glu Arg Val Ala Asn Ile Leu His Asp Asp Cys Ala Phe Leu 180 185 190 Ser Ala Phe Gly Asp Val Ser Lys Pro Glu Arg Tyr Ser Gly Asp Asn 195 200 205 Ile Ile Tyr Lys Pro Pro Gly His Ser Ala Pro Asp Met Val Tyr Leu 210 215 220 Gly Ala Met Thr Asn Phe Asp Val Thr Tyr Asn Trp Ile Gln Asp Lys 225 230 235 240 Cys Val Pro Leu Val Arg Glu Ile Thr Phe Glu Asn Gly Glu Glu Leu 245 250 255 Thr Glu Glu Gly Leu Pro Phe Leu Ile Leu Phe His Met Lys Glu Asp 260 265 270 Thr Glu Ser Leu Glu Ile Phe Gln Asn Glu Val Ala Arg Gln Leu Ile 275 280 285 Ser Glu Lys Gly Thr Ile Asn Phe Leu His Ala Asp Cys Asp Lys Phe 290 295 300 Arg His Pro Leu Leu His Ile Gln Lys Thr Pro Ala Asp Cys Pro Val 305 310 315 320 Ile Ala Ile Asp Ser Phe Arg His Met Tyr Val Phe Gly Asp Phe Lys 325 330 335 Asp Val Leu Ile Pro Gly Lys Leu Lys Gln Phe Val Phe Asp Leu His 340 345 350 Ser Gly Lys Leu His Arg Glu Phe His His Gly Pro Asp Pro Thr Asp 355 360 365 Thr Ala Pro Gly Glu Gln Ala Gln Asp Val Ala Ser Ser Pro Pro Glu 370 375 380 Ser Ser Phe Gln Lys Leu Ala Pro Ser Glu Tyr Arg Tyr Thr Leu Leu 385 390 395 400 Arg Asp Arg Asp Glu Leu 405 9 1272 DNA human 9 gcctttcgcg cttctgccgt ggccctctgc gggccgctcc gccggtgctg tccctgggcg 60 cctccgtgct ctcagccaac cgcctctgag agcgcccact cgagcgcccc gggagccaga 120 gggcgggggt cctcgccggg accctcctgt gggcccaggg ggacaaaagt ggctctcaat 180 ccagcacatg cacattgaag caagttaaag gatttaatat gaagcacaga agcagatagt 240 gccaaatagc aagcagtagt tgttacacat ttggtgagca gggcagcatt tccttctccc 300 actgctgctg agatggcaga aattagtcga attcagtacg aaatggaata tactgaaggc 360 attagtcagc gaatgagggt cccagaaaag ttaaaagtag caccgccaaa cgctgacctg 420 gaacaaggat tccaagaagg agttccaaat gctagtgtga taatgcaagt tccggagagg 480 attgttgtag caggaaataa tgaagatgtt tcattttcaa gaccagcaga tcttgacctt 540 attcagtcaa ctccctttaa acccctggca ctgaaaacac cacctcgtgt acttacgctg 600 agtgaaagac cactagattt tctggattta gaaagacctc ctacaacccc tcaaaatgaa 660 gaaatccgag cagttggcag actaaaaaga gagcggtcta tgagtgaaaa tgctgttcgc 720 caaaatggac agctggtcag aaatgattct cttgtgacac catcgccaca acaggctcgg 780 gtctgtcctc cccatatgtt acctgaagat ggagctaatc tttcctctgc tcgtggcatt 840 ttgtcgctta tccagtcttc tactcgtagg gcataccagc agatcttgga tgtgctggat 900 gaaaatcgca gacctgtgtt gcgtggtggg tctgctgccg ccacttctaa tcctcatcat 960 gacaacgtca ggtatggcat ttcaaatata gatacaacca ttgaaggaac gtcagatgac 1020 ctgactgttg tagatgcagc ttcactaaga cgacagataa tcaaactaaa tagacgtcta 1080 caacttctgg aagaggagaa caaagaacgt gctaaaagag aaatggtcat gtattcaatt 1140 actgtagctt tctggctgct taatagctgg ctctggtttc gccgctagag gtaacatcag 1200 ccctcaaaaa tactgtctca acagctggaa atataaaaga tttgcaaact tcaaaaaaaa 1260 aaaaaaaaaa aa 1272 10 291 PRT human 10 Met Ala Glu Ile Ser Arg Ile Gln Tyr Glu Met Glu Tyr Thr Glu Gly 1 5 10 15 Ile Ser Gln Arg Met Arg Val Pro Glu Lys Leu Lys Val Ala Pro Pro 20 25 30 Asn Ala Asp Leu Glu Gln Gly Phe Gln Glu Gly Val Pro Asn Ala Ser 35 40 45 Val Ile Met Gln Val Pro Glu Arg Ile Val Val Ala Gly Asn Asn Glu 50 55 60 Asp Val Ser Phe Ser Arg Pro Ala Asp Leu Asp Leu Ile Gln Ser Thr 65 70 75 80 Pro Phe Lys Pro Leu Ala Leu Lys Thr Pro Pro Arg Val Leu Thr Leu 85 90 95 Ser Glu Arg Pro Leu Asp Phe Leu Asp Leu Glu Arg Pro Pro Thr Thr 100 105 110 Pro Gln Asn Glu Glu Ile Arg Ala Val Gly Arg Leu Lys Arg Glu Arg 115 120 125 Ser Met Ser Glu Asn Ala Val Arg Gln Asn Gly Gln Leu Val Arg Asn 130 135 140 Asp Ser Leu Val Thr Pro Ser Pro Gln Gln Ala Arg Val Cys Pro Pro 145 150 155 160 His Met Leu Pro Glu Asp Gly Ala Asn Leu Ser Ser Ala Arg Gly Ile 165 170 175 Leu Ser Leu Ile Gln Ser Ser Thr Arg Arg Ala Tyr Gln Gln Ile Leu 180 185 190 Asp Val Leu Asp Glu Asn Arg Arg Pro Val Leu Arg Gly Gly Ser Ala 195 200 205 Ala Ala Thr Ser Asn Pro His His Asp Asn Val Arg Tyr Gly Ile Ser 210 215 220 Asn Ile Asp Thr Thr Ile Glu Gly Thr Ser Asp Asp Leu Thr Val Val 225 230 235 240 Asp Ala Ala Ser Leu Arg Arg Gln Ile Ile Lys Leu Asn Arg Arg Leu 245 250 255 Gln Leu Leu Glu Glu Glu Asn Lys Glu Arg Ala Lys Arg Glu Met Val 260 265 270 Met Tyr Ser Ile Thr Val Ala Phe Trp Leu Leu Asn Ser Trp Leu Trp 275 280 285 Phe Arg Arg 290 11 1585 DNA human 11 gcggcccggg cgggctgctc ggcgcggaac agtgctcggc atggcaggga ttccagggct 60 cctcttcctt ctcttctttc tgctctgtgc tgttgggcaa gtgagccctt acagtgcccc 120 ctggaaaccc acttggcctg cataccgcct ccctgtcgtc ttgccccagt ctaccctcaa 180 tttagccaag ccagactttg gagccgaagc caaattagaa gtatcttctt catgtggacc 240 ccagtgtcat aagggaactc cactgcccac ttacgaagag gccaagcaat atctgtctta 300 tgaaacgctc tatgccaatg gcagccgcac agagacgcag gtgggcatct acatcctcag 360 cagtagtgga gatggggccc aacaccgaga ctcagggtct tcaggaaagt ctcgaaggaa 420 gcggcagatt tatggctatg acagcaggtt cagcattttt gggaaggact tcctgctcaa 480 ctaccctttc tcaacatcag tgaagttatc cacgggctgc accggcaccc tggtggcaga 540 gaagcatgtc ctcacagctg cccactgcat acacgatgga aaaacctatg tgaaaggaac 600 ccagaagctt cgagtgggct tcctaaagcc caagtttaaa gatggtggtc gaggggccaa 660 cgactccact tcagccatgc ccgagcagat gaaatttcag tggatccggg tgaaacgcac 720 ccatgtgccc aagggttgga tcaagggcaa tgccaatgac atcggcatgg attatgatta 780 tgccctcctg gaactcaaaa agccccacaa gagaaaattt atgaagattg gggtgagccc 840 tcctgctaag cagctgccag ggggcagaat tcacttctct ggttatgaca atgaccgacc 900 aggcaatttg gtgtatcgct tctgtgacgt caaagacgag acctatgact tgctctacca 960 gcaatgcgat gcccagccag gggccagcgg gtctggggtc tatgtgagga tgtggaagag 1020 acagcagcag aagtgggagc gaaaaattat tggcattttt tcagggcacc agtgggtgga 1080 catgaatggt tccccacagg atttcaacgt ggctgtcaga atcactcctc tcaaatatgc 1140 ccagatttgc tattggatta aaggaaacta cctggattgt agggaggggt gacacagtgt 1200 tccctcctgg cagcaattaa gggtcttcat gttcttattt taggagaggc caaattgttt 1260 tttgtcattg gcgtgcacac gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtaaggtgtc 1320 ttataatctt ttacctattt cttacaattg caagatgact ggctttacta tttgaaaact 1380 ggtttgtgta tcatatcata tatcatttaa gcagtttgaa ggcatacttt tgcatagaaa 1440 taaaaaaaat actgatttgg ggcaatgagg aatatttgac aattaagtta atcttcacgt 1500 ttttgcaaac tttgattttt atttcatctg aacttgtttc aaagatttat attaaatatt 1560 tggcatacaa gagaaaaaaa aaaaa 1585 12 383 PRT human 12 Met Ala Gly Ile Pro Gly Leu Leu Phe Leu Leu Phe Phe Leu Leu Cys 1 5 10 15 Ala Val Gly Gln Val Ser Pro Tyr Ser Ala Pro Trp Lys Pro Thr Trp 20 25 30 Pro Ala Tyr Arg Leu Pro Val Val Leu Pro Gln Ser Thr Leu Asn Leu 35 40 45 Ala Lys Pro Asp Phe Gly Ala Glu Ala Lys Leu Glu Val Ser Ser Ser 50 55 60 Cys Gly Pro Gln Cys His Lys Gly Thr Pro Leu Pro Thr Tyr Glu Glu 65 70 75 80 Ala Lys Gln Tyr Leu Ser Tyr Glu Thr Leu Tyr Ala Asn Gly Ser Arg 85 90 95 Thr Glu Thr Gln Val Gly Ile Tyr Ile Leu Ser Ser Ser Gly Asp Gly 100 105 110 Ala Gln His Arg Asp Ser Gly Ser Ser Gly Lys Ser Arg Arg Lys Arg 115 120 125 Gln Ile Tyr Gly Tyr Asp Ser Arg Phe Ser Ile Phe Gly Lys Asp Phe 130 135 140 Leu Leu Asn Tyr Pro Phe Ser Thr Ser Val Lys Leu Ser Thr Gly Cys 145 150 155 160 Thr Gly Thr Leu Val Ala Glu Lys His Val Leu Thr Ala Ala His Cys 165 170 175 Ile His Asp Gly Lys Thr Tyr Val Lys Gly Thr Gln Lys Leu Arg Val 180 185 190 Gly Phe Leu Lys Pro Lys Phe Lys Asp Gly Gly Arg Gly Ala Asn Asp 195 200 205 Ser Thr Ser Ala Met Pro Glu Gln Met Lys Phe Gln Trp Ile Arg Val 210 215 220 Lys Arg Thr His Val Pro Lys Gly Trp Ile Lys Gly Asn Ala Asn Asp 225 230 235 240 Ile Gly Met Asp Tyr Asp Tyr Ala Leu Leu Glu Leu Lys Lys Pro His 245 250 255 Lys Arg Lys Phe Met Lys Ile Gly Val Ser Pro Pro Ala Lys Gln Leu 260 265 270 Pro Gly Gly Arg Ile His Phe Ser Gly Tyr Asp Asn Asp Arg Pro Gly 275 280 285 Asn Leu Val Tyr Arg Phe Cys Asp Val Lys Asp Glu Thr Tyr Asp Leu 290 295 300 Leu Tyr Gln Gln Cys Asp Ala Gln Pro Gly Ala Ser Gly Ser Gly Val 305 310 315 320 Tyr Val Arg Met Trp Lys Arg Gln Gln Gln Lys Trp Glu Arg Lys Ile 325 330 335 Ile Gly Ile Phe Ser Gly His Gln Trp Val Asp Met Asn Gly Ser Pro 340 345 350 Gln Asp Phe Asn Val Ala Val Arg Ile Thr Pro Leu Lys Tyr Ala Gln 355 360 365 Ile Cys Tyr Trp Ile Lys Gly Asn Tyr Leu Asp Cys Arg Glu Gly 370 375 380 13 1071 DNA human 13 cagtaagctc ggctcacagt cgcaggagag ttctggggta cacgggcaaa ggggcttgag 60 aaggcccgga ggcgaagccg aagagaagca actgtgcccc ggagaagaga agctcgccca 120 ttccagactg ggaaccagct ttcagtgaag atggcagggc cagaactgtt gctcgactcc 180 aacatccgcc tctgggtggt cctacccatc gttatcatca ctttcttcgt aggcatgatc 240 cgccactacg tgtccatcct gctgcagagc gacaagaagc tcacccagga acaagtatct 300 gacagtcaag tcctaattcg aagcagagtc ctcagggaaa atggaaaata cattcccaaa 360 cagtctttct tgacacgaaa atattatttc aacaacccag aggatggatt tttcaaaaaa 420 actaaacgga aggtagtgcc accttctcct atgactgatc ctactatgtt gacagacatg 480 atgaaaggga atgtaacaaa tgtcctccct atgattctta ttggtggatg gatcaacatg 540 acattctcag gctttgtcac aaccaaggtc ccatttccac tgaccctccg ttttaagcct 600 atgttacagc aaggaatcga gctactcaca ttagatgcat cctgggtgag ttctgcatcc 660 tggtacttcc tcaatgtatt tgggcttcgg agcatttact ctctgattct gggccaagat 720 aatgccgctg accaatcacg aatgatgcag gagcagatga cgggagcagc catggccatg 780 cccgcagaca caaacaaagc tttcaagaca gagtgggaag ctttggagct gacggatcac 840 cagtgggcac tagatgatgt cgaagaagag ctcatggcca aagacctcca cttcgaaggc 900 atgttcaaaa aggaattaca gacctctatt ttttgaagac cgagcaggga ttagctgtgt 960 caggaacttg gagttgcact taaccttgta actttgtttg gagctggcac ctcttgaaat 1020 aaaaaggagg atgcacgagc tggcaggcat gcaaaaaaaa aaaaaaaaaa a 1071 14 261 PRT human 14 Met Ala Gly Pro Glu Leu Leu Leu Asp Ser Asn Ile Arg Leu Trp Val 1 5 10 15 Val Leu Pro Ile Val Ile Ile Thr Phe Phe Val Gly Met Ile Arg His 20 25 30 Tyr Val Ser Ile Leu Leu Gln Ser Asp Lys Lys Leu Thr Gln Glu Gln 35 40 45 Val Ser Asp Ser Gln Val Leu Ile Arg Ser Arg Val Leu Arg Glu Asn 50 55 60 Gly Lys Tyr Ile Pro Lys Gln Ser Phe Leu Thr Arg Lys Tyr Tyr Phe 65 70 75 80 Asn Asn Pro Glu Asp Gly Phe Phe Lys Lys Thr Lys Arg Lys Val Val 85 90 95 Pro Pro Ser Pro Met Thr Asp Pro Thr Met Leu Thr Asp Met Met Lys 100 105 110 Gly Asn Val Thr Asn Val Leu Pro Met Ile Leu Ile Gly Gly Trp Ile 115 120 125 Asn Met Thr Phe Ser Gly Phe Val Thr Thr Lys Val Pro Phe Pro Leu 130 135 140 Thr Leu Arg Phe Lys Pro Met Leu Gln Gln Gly Ile Glu Leu Leu Thr 145 150 155 160 Leu Asp Ala Ser Trp Val Ser Ser Ala Ser Trp Tyr Phe Leu Asn Val 165 170 175 Phe Gly Leu Arg Ser Ile Tyr Ser Leu Ile Leu Gly Gln Asp Asn Ala 180 185 190 Ala Asp Gln Ser Arg Met Met Gln Glu Gln Met Thr Gly Ala Ala Met 195 200 205 Ala Met Pro Ala Asp Thr Asn Lys Ala Phe Lys Thr Glu Trp Glu Ala 210 215 220 Leu Glu Leu Thr Asp His Gln Trp Ala Leu Asp Asp Val Glu Glu Glu 225 230 235 240 Leu Met Ala Lys Asp Leu His Phe Glu Gly Met Phe Lys Lys Glu Leu 245 250 255 Gln Thr Ser Ile Phe 260 15 2520 DNA human 15 atggcggccg ccggggctgc ggctacacac ctagaggtgg cccggggcaa gcgcgccgcc 60 ctcttcttcg ctgcggtggc catcgtgctg gggctaccgc tctggtggaa gaccacggag 120 acctaccggg cctcgttgcc ttactcccag atcagtggcc tgaatgccct tcagctccgc 180 ctcatggtgc ctgtcactgt cgtgtttacg cgggagtcag tgcccctgga cgaccaggag 240 aagctgccct tcaccgttgt gcatgaaaga gagattcctc tgaaatacaa aatgaaaatc 300 aaatgccgtt tccagaaggc ctatcggagg gctttggacc atgaggagga ggccctgtca 360 tcgggcagtg tgcaagaggc agaagccatg ttagatgagc ctcaggaaca agcggagggc 420 tccctgactg tgtacgtgat atctgaacac tcctcacttc ttccccagga catgatgagc 480 tacattgggc ccaagaggac agcagtggtg cgggggataa tgcaccggga ggcctttaac 540 atcattggcc gccgcatagt ccaggtggcc caggccatgt ctttgactga ggatgtgctt 600 gctgctgctc tggctgacca ccttccagag gacaagtgga gcgctgagaa gaggcggcct 660 ctcaagtcca gcttgggcta tgagatcacc ttcagtttac tcaacccaga ccccaagtcc 720 catgatgtct actgggacat tgagggggct gtccggcgct atgtgcaacc tttcctgaat 780 gccctcggtg ccgctggcaa cttctctgtg gactctcaga ttctttacta tgcaatgttg 840 ggggtgaatc cccgctttga ctcagcttcc tccagctact atttggacat gcacagcctc 900 ccccatgtca tcaacccagt ggagtcccgg ctgggatcca gtgctgcctc cttgtaccct 960 gtgctcaact ttctactcta cgtgcctgag cttgcacact caccgctgta cattcaggac 1020 aaggatggcg ctccagtggc caccaatgcc ttccatagtc cccgctgggg tggcattatg 1080 gtatataatg ttgactccaa aacctataat gcctcagtgc tgccagtgag agtcgaggtg 1140 gacatggtgc gagtgatgga ggtgttcctg gcacagttgc ggttgctctt tgggattgct 1200 cagccccagc tgcctccaaa atgcctgctt tcagggccta cgagtgaagg gctaatgacc 1260 tgggagctag accggctgct ctgggctcgg tcagtggaga acctggccac agccaccacc 1320 acccttacct ccctggcgca gcttctgggc aagatcagca acattgtcat taaggacgac 1380 gtggcatctg aggtgtacaa ggctgtagct gccgtccaga agtcggcaga agagttggcg 1440 tctgggcacc tggcatctgc ctttgtcgcc agccaggaag ctgtgacatc ctctgagctt 1500 gccttctttg acccgtcact cctccacctc ctttatttcc ctgatgacca gaagtttgcc 1560 atctacatcc cactcttcct gcctatggct gtgcccatcc tcctgtccct ggtcaagatc 1620 ttcctggaga cccgcaagtc ctggagaaag cctgagaaga cagactgagc agggcagcac 1680 ctccatagga agccttcctt tctggccaag gtgggcggtg ttagattgtg aggcacgtac 1740 atggggcctg ccggaatgac ttaaatattt gtctccagtc tccactgttg gctctccagc 1800 aaccaaagta caacactcca agatgggttc atcttttctt cctttcccat tcacctggct 1860 caatcctcct ccaccaccag gggcctcaaa aggcacatca tccgggtctc cttatcttgt 1920 ttgataaggc tgctgcctgt ctccctctgt ggcaaggact gtttgttctt ttgccccatt 1980 tctcaacata gcacacttgt gcactgagag gagggagcat tatgggaaag tccctgcctt 2040 ccacacctct ctctagtccc tgtgggacag ccctagcccc tgctgtcatg aaggggccag 2100 gcattggtca cctgtgggac cttctccctc actcccctcc ctcctagttg gctttgtctg 2160 tcaggtgcag tctggcggga gtccaggagg cagcagctca ggacatggtg ctgtgtgtgt 2220 gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt cagaggttcc agaaagttcc agatttggaa 2280 tcaaacagtc ctgaattcaa atccttgttt ttgcacttat tgtctggaga gctttggata 2340 aggtattgaa tctctctgag cctcagtttt tcatttgttc aaatggcact gatgatgtct 2400 cccttacaag atggttgtga ggagtaaatg tgatcagcat gtaaagtgtc tggcgtgtag 2460 taggctctta ataaacactg gctgaatatg aattggaatg ataaaaaaaa aaaaaaaaaa 2520 16 555 PRT human 16 Met Ala Ala Ala Gly Ala Ala Ala Thr His Leu Glu Val Ala Arg Gly 1 5 10 15 Lys Arg Ala Ala Leu Phe Phe Ala Ala Val Ala Ile Val Leu Gly Leu 20 25 30 Pro Leu Trp Trp Lys Thr Thr Glu Thr Tyr Arg Ala Ser Leu Pro Tyr 35 40 45 Ser Gln Ile Ser Gly Leu Asn Ala Leu Gln Leu Arg Leu Met Val Pro 50 55 60 Val Thr Val Val Phe Thr Arg Glu Ser Val Pro Leu Asp Asp Gln Glu 65 70 75 80 Lys Leu Pro Phe Thr Val Val His Glu Arg Glu Ile Pro Leu Lys Tyr 85 90 95 Lys Met Lys Ile Lys Cys Arg Phe Gln Lys Ala Tyr Arg Arg Ala Leu 100 105 110 Asp His Glu Glu Glu Ala Leu Ser Ser Gly Ser Val Gln Glu Ala Glu 115 120 125 Ala Met Leu Asp Glu Pro Gln Glu Gln Ala Glu Gly Ser Leu Thr Val 130 135 140 Tyr Val Ile Ser Glu His Ser Ser Leu Leu Pro Gln Asp Met Met Ser 145 150 155 160 Tyr Ile Gly Pro Lys Arg Thr Ala Val Val Arg Gly Ile Met His Arg 165 170 175 Glu Ala Phe Asn Ile Ile Gly Arg Arg Ile Val Gln Val Ala Gln Ala 180 185 190 Met Ser Leu Thr Glu Asp Val Leu Ala Ala Ala Leu Ala Asp His Leu 195 200 205 Pro Glu Asp Lys Trp Ser Ala Glu Lys Arg Arg Pro Leu Lys Ser Ser 210 215 220 Leu Gly Tyr Glu Ile Thr Phe Ser Leu Leu Asn Pro Asp Pro Lys Ser 225 230 235 240 His Asp Val Tyr Trp Asp Ile Glu Gly Ala Val Arg Arg Tyr Val Gln 245 250 255 Pro Phe Leu Asn Ala Leu Gly Ala Ala Gly Asn Phe Ser Val Asp Ser 260 265 270 Gln Ile Leu Tyr Tyr Ala Met Leu Gly Val Asn Pro Arg Phe Asp Ser 275 280 285 Ala Ser Ser Ser Tyr Tyr Leu Asp Met His Ser Leu Pro His Val Ile 290 295 300 Asn Pro Val Glu Ser Arg Leu Gly Ser Ser Ala Ala Ser Leu Tyr Pro 305 310 315 320 Val Leu Asn Phe Leu Leu Tyr Val Pro Glu Leu Ala His Ser Pro Leu 325 330 335 Tyr Ile Gln Asp Lys Asp Gly Ala Pro Val Ala Thr Asn Ala Phe His 340 345 350 Ser Pro Arg Trp Gly Gly Ile Met Val Tyr Asn Val Asp Ser Lys Thr 355 360 365 Tyr Asn Ala Ser Val Leu Pro Val Arg Val Glu Val Asp Met Val Arg 370 375 380 Val Met Glu Val Phe Leu Ala Gln Leu Arg Leu Leu Phe Gly Ile Ala 385 390 395 400 Gln Pro Gln Leu Pro Pro Lys Cys Leu Leu Ser Gly Pro Thr Ser Glu 405 410 415 Gly Leu Met Thr Trp Glu Leu Asp Arg Leu Leu Trp Ala Arg Ser Val 420 425 430 Glu Asn Leu Ala Thr Ala Thr Thr Thr Leu Thr Ser Leu Ala Gln Leu 435 440 445 Leu Gly Lys Ile Ser Asn Ile Val Ile Lys Asp Asp Val Ala Ser Glu 450 455 460 Val Tyr Lys Ala Val Ala Ala Val Gln Lys Ser Ala Glu Glu Leu Ala 465 470 475 480 Ser Gly His Leu Ala Ser Ala Phe Val Ala Ser Gln Glu Ala Val Thr 485 490 495 Ser Ser Glu Leu Ala Phe Phe Asp Pro Ser Leu Leu His Leu Leu Tyr 500 505 510 Phe Pro Asp Asp Gln Lys Phe Ala Ile Tyr Ile Pro Leu Phe Leu Pro 515 520 525 Met Ala Val Pro Ile Leu Leu Ser Leu Val Lys Ile Phe Leu Glu Thr 530 535 540 Arg Lys Ser Trp Arg Lys Pro Glu Lys Thr Asp 545 550 555 17 1245 DNA human 17 ctacatcctg gacaacgaga ccaacttcgt ggtccaggtc agcgtcttca ttggggtcct 60 catcgacctc tggaagatca ccaaggtcat ggacgtccgg ctggaccgag agcacagggt 120 ggcaggaatc ttcccccgcc tatccttcaa ggacaagtcc acgtatatcg agtcctcgac 180 caaagtgtat gatgatatgg cattccggta cctgtcctgg atcctcttcc cgctcctggg 240 ctgctatgcc gtctacagtc ttctgtacct ggagcacaag ggctggtact cctgggtgct 300 cagcatgctc tacggcttcc tgctgacctt cggcttcatc accatgacgc cccagctctt 360 catcaactac aagctcaagt ctgtggccca ccttccctgg cgcatgctca cctacaaggc 420 cctcaacaca ttcatcgacg acctgttcgc ctttgtcatc aagatgcccg ttatgtaccg 480 gatcggctgc ctgcgggacg atgtggtttt cttcatctac ctctaccaac ggtggatcta 540 ccgcgtcgac cccacccgag tcaacgagtt tggcatgagt ggagaagacc ccacagctgc 600 cgcccccgtg gccgaggttc ccacagcagc aggggccctc acgcccacac ctgcacccac 660 cacgaccacc gccaccaggg aggaggcctc cacgtccctg cccaccaagc ccacccaggg 720 ggccagctct gccagcgagc cccaggaagc ccctccaaag ccagcagagg acaagaaaaa 780 ggattagtcg agactggtcc tcacctgctc cggctcctgg cgaccactac ccctgcgtcc 840 cggccccctc gcctcccctc cctgtcgccc tttccctgga cagatcaggc cggggcggtg 900 ggaggcccgc ctcaggtcag ggcccagcgt gtgatgtagg ggccggggca ggccagggtt 960 tgtttgtgga ggcgctgtct gtccctctgt ccctctgtgt ttccagccat ctcgccctgc 1020 cagcccagca ccactgggaa tcatggtgaa gctgatgcag cgttgccgag ggggtgggtt 1080 gggcgggggt ggggccgggc ccccctaggg gatgccccgg gccgttcatc atcttgtccc 1140 tggtccccct accacactcc ccctcctaaa ccgccgccct ttaacacagt ttggatttaa 1200 taaattcaga tgggggttta acttaaactc aaaaaaaaaa aaaaa 1245 18 232 PRT human 18 Met Asp Val Arg Leu Asp Arg Glu His Arg Val Ala Gly Ile Phe Pro 1 5 10 15 Arg Leu Ser Phe Lys Asp Lys Ser Thr Tyr Ile Glu Ser Ser Thr Lys 20 25 30 Val Tyr Asp Asp Met Ala Phe Arg Tyr Leu Ser Trp Ile Leu Phe Pro 35 40 45 Leu Leu Gly Cys Tyr Ala Val Tyr Ser Leu Leu Tyr Leu Glu His Lys 50 55 60 Gly Trp Tyr Ser Trp Val Leu Ser Met Leu Tyr Gly Phe Leu Leu Thr 65 70 75 80 Phe Gly Phe Ile Thr Met Thr Pro Gln Leu Phe Ile Asn Tyr Lys Leu 85 90 95 Lys Ser Val Ala His Leu Pro Trp Arg Met Leu Thr Tyr Lys Ala Leu 100 105 110 Asn Thr Phe Ile Asp Asp Leu Phe Ala Phe Val Ile Lys Met Pro Val 115 120 125 Met Tyr Arg Ile Gly Cys Leu Arg Asp Asp Val Val Phe Phe Ile Tyr 130 135 140 Leu Tyr Gln Arg Trp Ile Tyr Arg Val Asp Pro Thr Arg Val Asn Glu 145 150 155 160 Phe Gly Met Ser Gly Glu Asp Pro Thr Ala Ala Ala Pro Val Ala Glu 165 170 175 Val Pro Thr Ala Ala Gly Ala Leu Thr Pro Thr Pro Ala Pro Thr Thr 180 185 190 Thr Thr Ala Thr Arg Glu Glu Ala Ser Thr Ser Leu Pro Thr Lys Pro 195 200 205 Thr Gln Gly Ala Ser Ser Ala Ser Glu Pro Gln Glu Ala Pro Pro Lys 210 215 220 Pro Ala Glu Asp Lys Lys Lys Asp 225 230 19 1030 DNA human 19 aacatggaga ctttgtaccg tgtcccgttc ttagtgctcg aatgtcccaa cctgaagctg 60 aagaagccgc cctggttgca catgccgtcg gccatgactg tgtatgctct ggtggtggtg 120 tcttacttcc tcatcaccgg aggaataatt tatgatgtta ttgttgaacc tccaagtgtc 180 ggttctatga ctgatgaaca tgggcatcag aggccagtag ctttcttggc ctacagagta 240 aatggacaat atattatgga aggacttgca tccagcttcc tatttacaat gggaggttta 300 ggtttcataa tcctggaccg atcgaatgca ccaaatatcc caaaactcaa tagattcctt 360 cttctgttca ttggattcgt ctgtgtccta ttgagttttt tcatggctag agtattcatg 420 agaatgaaac tgccgggcta tctgatgggt tagagtgcct ttgagaagaa atcagtggat 480 actggatttg ctcctgtcaa tgaagtttta aaggctgtac caatcctcta atatgaaatg 540 tggaaaagaa tgaagagcag cagtaaaaga aatatctagt gaaaaaacag gaagcgtatt 600 gaagcttgga ctagaatttc ttcttggtat taaagagaca agtttatcac agaatttttt 660 ttcctgctgg cctattgcta taccaatgat gttgagtggc attttctttt tagtttttca 720 ttaaaatata ttccatatct acaactataa tatcaaataa agtgattatt ttttacaacc 780 ctcttaacat tttttggaga tgacatttct gattttcaga aattaacata aaatccagaa 840 gcaagattcc gtaagctgag aactctggac agttgatcag ctttacctat ggtgctttgc 900 ctttaactag agtgtgtgat ggtagattat ttcagatatg tatgtaaaac tgtttcctga 960 acaataagat gtatgaacgg agcagaaata aatacttttt ctaattaata cctttaaaaa 1020 aaaaaaaaaa 1030 20 149 PRT human 20 Met Glu Thr Leu Tyr Arg Val Pro Phe Leu Val Leu Glu Cys Pro Asn 1 5 10 15 Leu Lys Leu Lys Lys Pro Pro Trp Leu His Met Pro Ser Ala Met Thr 20 25 30 Val Tyr Ala Leu Val Val Val Ser Tyr Phe Leu Ile Thr Gly Gly Ile 35 40 45 Ile Tyr Asp Val Ile Val Glu Pro Pro Ser Val Gly Ser Met Thr Asp 50 55 60 Glu His Gly His Gln Arg Pro Val Ala Phe Leu Ala Tyr Arg Val Asn 65 70 75 80 Gly Gln Tyr Ile Met Glu Gly Leu Ala Ser Ser Phe Leu Phe Thr Met 85 90 95 Gly Gly Leu Gly Phe Ile Ile Leu Asp Arg Ser Asn Ala Pro Asn Ile 100 105 110 Pro Lys Leu Asn Arg Phe Leu Leu Leu Phe Ile Gly Phe Val Cys Val 115 120 125 Leu Leu Ser Phe Phe Met Ala Arg Val Phe Met Arg Met Lys Leu Pro 130 135 140 Gly Tyr Leu Met Gly 145 21 1563 DNA human 21 gttgattggg tctagaccaa agaactttga ggaacttgcc cagagccctg catgcatcag 60 cctacagca gacattgcag gcctgaagaa aggtggtcac aagaggggtg gaacattcct 120 gcaaatggtt tcaatatatg cagatgtctc gatataggaa tgaaattacg tctttggaac 180 aacttaaata agtcaaatat acttggagct ttaaaaatta aaaggagaga gattcgagca 240 ccttttctgc tgccatgaca accatgcaag gaatggaaca ggccatgcca ggggctggcc 300 ctggtgtgcc ccagctggga aacatggctg tcatacattc acatctgtgg aaaggattgc 360 aagagaagtt cttgaaggga gaacccaaag tccttggggt tgtgcagatt ctgactgccc 420 tgatgagcct tagcatggga ataacaatga tgtgtatggc atctaatact tatggaagta 480 accctatttc cgtgtatatc gggtacacaa tttgggggtc agtaatgttt attatttcag 540 gatccttgtc aattgcagca ggaattagaa ctacaaaagg cctgggtctg gatggcatgg 600 tgctcctctt aagtgtgctg gaattctgca ttgctgtgtc cctctctgcc tttggatgta 660 aagtgctctg ttgtacccct ggtggggttg tgttaattct gccatcacat tctcacatgg 720 cagaaacagc atctcccaca ccacttaatg aggtttgagg ccaccaaaag atcaacagac 780 aaatgctcca gaaatctatg ctgactgtga cacaagagcc tcacatgaga aattaccagt 840 atccaacttc gatactgata gacttgttga tattattatt atatgtaatc caattatgaa 900 ctgtgtgtgt atagagagat aataaattca aaattatgtt ctcatttttt tccctggaac 960 tcaataactc atttcactgg ctctttatcg agagtactag aagttaaatt aataaataat 020 gcatttaatg aggcaacagc acttgaaagt ttttcattca tcataagaac tttatataaa 080 ggcattacat tggcaaataa ggtttggaag cagaagagca aaaaaaagat attgttaaaa 140 tgaggcctcc atgcaaaaca catacttccc tcccatttat ttaacttttt tttttctcct 1200 acctatgggg accaaagtgc tttttccttc aggaagtgga gatgcatggc catctccccc 1260 tccctttttc cttctcctgc ttttctttcc ccatagaaag taccttgaag tagcacagtc 1320 cgtccttgca tgtgcacgag ctatcatttg agtaaaagta tacatggagt aaaaatcata 1380 ttaagcatca gattcaactt atattttcta tttcatcttc ttcctttccc ttctcccacc 1440 ttctactggg cataattata tcttaatcat atatggaaat gtgcaacata tggtatttgt 1500 taaatacgtt tgtttttatt gcagagcaaa aataaatcaa attagaagca aaaaaaaaaa 1560 aaa 1563 22 167 PRT human 22 Met Thr Thr Met Gln Gly Met Glu Gln Ala Met Pro Gly Ala Gly Pro 1 5 10 15 Gly Val Pro Gln Leu Gly Asn Met Ala Val Ile His Ser His Leu Trp 20 25 30 Lys Gly Leu Gln Glu Lys Phe Leu Lys Gly Glu Pro Lys Val Leu Gly 35 40 45 Val Val Gln Ile Leu Thr Ala Leu Met Ser Leu Ser Met Gly Ile Thr 50 55 60 Met Met Cys Met Ala Ser Asn Thr Tyr Gly Ser Asn Pro Ile Ser Val 65 70 75 80 Tyr Ile Gly Tyr Thr Ile Trp Gly Ser Val Met Phe Ile Ile Ser Gly 85 90 95 Ser Leu Ser Ile Ala Ala Gly Ile Arg Thr Thr Lys Gly Leu Gly Leu 100 105 110 Asp Gly Met Val Leu Leu Leu Ser Val Leu Glu Phe Cys Ile Ala Val 115 120 125 Ser Leu Ser Ala Phe Gly Cys Lys Val Leu Cys Cys Thr Pro Gly Gly 130 135 140 Val Val Leu Ile Leu Pro Ser His Ser His Met Ala Glu Thr Ala Ser 145 150 155 160 Pro Thr Pro Leu Asn Glu Val 165 23 2590 DNA human 23 ccggcgggac ggagggcccg gcaggaagat gggctcccgt ggacagggac tcttgctggc 60 gtactgcctg ctccttgcct ttgcctctgg cctggtcctg agtcgtgtgc cccatgtcca 120 gggggaacag caggagtggg aggggactga ggagctgccg tcgcctccgg accatgccga 180 gagggctgaa gaacaacatg aaaaatacag gcccagtcag gaccaggggc tccctgcttc 240 ccggtgcttg cgctgctgtg accccggtac ctccatgtac ccggcgaccg ccgtgcccca 300 gatcaacatc actatcttga aaggggagaa gggtgaccgc ggagatcgag gcctccaagg 360 gaaatatggc aaaacaggct cagcaggggc caggggccac actggaccca aagggcagaa 420 gggctccatg ggggcccctg gggagcggtg caagagccac tacgccgcct tttcggtggg 480 ccggaagaag cccatgcaca gcaaccacta ctaccagacg gtgatcttcg acacggagtt 540 cgtgaacctc tacgaccact tcaacatgtt caccggcaag ttctactgct acgtgcccgg 600 cctctacttc ttcagcctca acgtgcacac ctggaaccag aaggagacct acctgcacat 660 catgaagaac gaggaggagg tggtgatctt gttcgcgcag gtgggcgacc gcagcatcat 720 gcaaagccag agcctgatgc tggagctgcg agagcaggac caggtgtggg tacgcctcta 780 caagggcgaa cgtgagaacg ccatcttcag cgaggagctg gacacctaca tcaccttcag 840 tggctacctg gtcaagcacg ccaccgagcc ctagctggcc ggccacctcc tttcctctcg 900 ccaccttcca cccctgcgct gtgctgaccc caccgcctct tccccgatcc ctggactccg 960 actccctggc tttggcattc agtgagacgc cctgcacaca cagaaagcca aagcgatcgg 1020 tgctcccaga tcccgcagcc tctggagaga gctgacggca gatgaaatca ccagggcggg 1080 gcacccgcga gaaccctctg ggaccttccg cggccctctc tgcacacatc ctcaagtgac 1140 cccgcacggc gagacgcggg tggcggcagg gcgtcccagg gtgcggcacc gcggctccag 1200 tccttggaaa taattaggca aattctaaag gtctcaaaag gagcaaagta aaccgtggag 1260 gacaaagaaa agggttgtta tttttgtctt tccagccagc ctgctggctc ccaagagaga 1320 ggccttttca gttgagactc tgcttaagag aagatccaaa gttaaagctc tggggtcagg 1380 ggaggggccg ggggcaggaa actacctctg gcttaattct tttaagccac gtaggaactt 1440 tcttgaggga taggtggacc ctgacatccc tgtggccttg cccaagggct ctgctggtct 1500 ttctgagtca cagctgcgag gtgatggggg ctggggcccc aggcgtcagc ctcccagagg 1560 gacagctgag ccccctgcct tggctccagg ttggtagaag cagccgaagg gctcctgaca 1620 gtggccaggg acccctgggt cccccaggcc tgcagatgtt tctatgaggg gcagagctcc 1680 tggtacatcc atgtgtggct ctgctccacc cctgtgccac cccagagccc tggggggtgg 1740 tctccatgcc tgccaccctg gcatcggctt tctgtgccgc ctcccacaca aatcagcccc 1800 agaaggcccc ggggccttgg cttctgtttt ttataaaaca cctcaagcag cactgcagtc 1860 tcccatctcc tcgtgggcta agcatcaccg cttccacgtg tgttgtgttg gttggcagca 1920 aggctgatcc agaccccttc tgcccccact gccctcatcc aggcctctga ccagtagcct 1980 gagaggggct ttttctaggc ttcagagcag gggagagctg gaaggggcta gaaagctccc 2040 gcttgtctgt ttctcaggct cctgtgagcc tcagtcctga gaccagagtc aagaggaagt 2100 acacgtccca atcacccgtg tcaggattca ctctcaggag ctgggtggca ggagaggcaa 2160 tagcccctgt ggcaattgca ggaccagctg gagcagggtt gcggtgtctc cacggtgctc 2220 tcgccctgcc catggccacc ccagactctg atctccagga accccatagc ccctctccac 2280 ctcaccccat gttgatgccc agggtcactc ttgctacccg ctgggccccc aaacccccgc 2340 tgcctctctt ccttcccccc atcccccacc tggttttgac taatcctgct tccctctctg 2400 ggcctggctg ccgggatctg gggtccctaa gtccctctct ttaaagaact tctgcgggtc 2460 agactctgaa gccgagttgc tgtgggcgtg cccggaagca gagcgccaca ctcgctgctt 2520 aagctccccc agctctttcc agaaaacatt aaactcagaa ttgtgttttc aaaaaaaaaa 2580 aaaaaaaaaa 2590 24 281 PRT human 24 Met Gly Ser Arg Gly Gln Gly Leu Leu Leu Ala Tyr Cys Leu Leu Leu 1 5 10 15 Ala Phe Ala Ser Gly Leu Val Leu Ser Arg Val Pro His Val Gln Gly 20 25 30 Glu Gln Gln Glu Trp Glu Gly Thr Glu Glu Leu Pro Ser Pro Pro Asp 35 40 45 His Ala Glu Arg Ala Glu Glu Gln His Glu Lys Tyr Arg Pro Ser Gln 50 55 60 Asp Gln Gly Leu Pro Ala Ser Arg Cys Leu Arg Cys Cys Asp Pro Gly 65 70 75 80 Thr Ser Met Tyr Pro Ala Thr Ala Val Pro Gln Ile Asn Ile Thr Ile 85 90 95 Leu Lys Gly Glu Lys Gly Asp Arg Gly Asp Arg Gly Leu Gln Gly Lys 100 105 110 Tyr Gly Lys Thr Gly Ser Ala Gly Ala Arg Gly His Thr Gly Pro Lys 115 120 125 Gly Gln Lys Gly Ser Met Gly Ala Pro Gly Glu Arg Cys Lys Ser His 130 135 140 Tyr Ala Ala Phe Ser Val Gly Arg Lys Lys Pro Met His Ser Asn His 145 150 155 160 Tyr Tyr Gln Thr Val Ile Phe Asp Thr Glu Phe Val Asn Leu Tyr Asp 165 170 175 His Phe Asn Met Phe Thr Gly Lys Phe Tyr Cys Tyr Val Pro Gly Leu 180 185 190 Tyr Phe Phe Ser Leu Asn Val His Thr Trp Asn Gln Lys Glu Thr Tyr 195 200 205 Leu His Ile Met Lys Asn Glu Glu Glu Val Val Ile Leu Phe Ala Gln 210 215 220 Val Gly Asp Arg Ser Ile Met Gln Ser Gln Ser Leu Met Leu Glu Leu 225 230 235 240 Arg Glu Gln Asp Gln Val Trp Val Arg Leu Tyr Lys Gly Glu Arg Glu 245 250 255 Asn Ala Ile Phe Ser Glu Glu Leu Asp Thr Tyr Ile Thr Phe Ser Gly 260 265 270 Tyr Leu Val Lys His Ala Thr Glu Pro 275 280 25 1668 DNA human 25 ggacttgagc gagccagttg ccggattatt ctatttcccc tccctctctc ccgccccgta 60 tctcttttca cccttctccc accctcgctc gcgtagccat ggcggagccg tcggcggcca 120 ctcagtccca ttccatctcc tcgtcgtcct tcggagccga gccgtccgcg cccggcggcg 180 gcgggagccc aggagcctgc cccgccctgg ggacgaagag ctgcagctcc tcctgtgcgg 240 tgcacgatct gattttctgg agagatgtga agaagactgg gtttgtcttt ggcaccacgc 300 tgatcatgct gctttccctg gcagctttca gtgtcatcag tgtggtttct tacctcatcc 360 tggctcttct ctctgtcacc atcagcttca ggatctacaa gtccgtcatc caagctgtac 420 agaagtcaga agaaggccat ccattcaaag cctacctgga cgtagacatt actctgtcct 480 cagaagcttt ccataattac atgaatgctg ccatggtgca catcaacagg gccctgaaac 540 tcattattcg tctctttctg gtagaagatc tggttgactc cttgaagctg gctgtcttca 600 tgtggctgat gacctatgtt ggtgctgttt ttaacggaat cacccttcta attcttgctg 660 aactgctcat tttcagtgtc ccgattgtct atgagaagta caagacccag attgatcact 720 atgttggcat cgcccgagat cagaccaagt caattgttga aaagatccaa gcaaaactcc 780 ctggaatcgc caaaaaaaag gcagaataag tacatggaaa ccagaaatgc aacagttact 840 aaaacaccat ttaatagtta taacgtcgtt acttgtacta tgaaggaaaa tactcagtgt 900 cagcttgagc ctgcattcca agcttttttt ttaatttggt gttttctccc atcctttccc 960 tttaaccctc agtatcaagc acaaaaattg atggactgat aaaagaacta tcttagaact 1020 cagaagaaga aagaatcaaa ttcataggat aagtcaatac cttaatggtg gtagagcctt 1080 tacctgtagc ttgaaagggg aaagattgga ggtaagagag aaaatgaaag aacacctctg 1140 ggtccttctg tccagttttc agcactagtc ttactcagct atccattata gttttgccct 1200 taagaagtca tgattaactt atgaaaaaat tatttgggga caggagtgtg ataccttcct 1260 tggttttttt ttgcagccct caaatcctat cttcctgccc cacaatgtga gcagctaccc 1320 ctgatactcc ttttctttaa tgatttaact atcaacttga taaataactt ataggtgata 1380 gtgataattc ctgattccaa gaatgccatc tgataaaaaa gaatagaaat ggaaagtggg 1440 actgagaggg agtcagcagg catgctgcgg tggcggtcac tccctctgcc actatcccca 1500 gggaaggaaa ggctccgcca tttgggaaag tggtttctac gtcactggac accggttctg 1560 agcattagtt tgagaactcg ttcccgaatg tgctttcctc cctctcccct gcccacctca 1620 agtttaataa ataaggttgt acttttctta ctataaaaaa aaaaaaaa 1668 26 236 PRT human 26 Met Ala Glu Pro Ser Ala Ala Thr Gln Ser His Ser Ile Ser Ser Ser 1 5 10 15 Ser Phe Gly Ala Glu Pro Ser Ala Pro Gly Gly Gly Gly Ser Pro Gly 20 25 30 Ala Cys Pro Ala Leu Gly Thr Lys Ser Cys Ser Ser Ser Cys Ala Val 35 40 45 His Asp Leu Ile Phe Trp Arg Asp Val Lys Lys Thr Gly Phe Val Phe 50 55 60 Gly Thr Thr Leu Ile Met Leu Leu Ser Leu Ala Ala Phe Ser Val Ile 65 70 75 80 Ser Val Val Ser Tyr Leu Ile Leu Ala Leu Leu Ser Val Thr Ile Ser 85 90 95 Phe Arg Ile Tyr Lys Ser Val Ile Gln Ala Val Gln Lys Ser Glu Glu 100 105 110 Gly His Pro Phe Lys Ala Tyr Leu Asp Val Asp Ile Thr Leu Ser Ser 115 120 125 Glu Ala Phe His Asn Tyr Met Asn Ala Ala Met Val His Ile Asn Arg 130 135 140 Ala Leu Lys Leu Ile Ile Arg Leu Phe Leu Val Glu Asp Leu Val Asp 145 150 155 160 Ser Leu Lys Leu Ala Val Phe Met Trp Leu Met Thr Tyr Val Gly Ala 165 170 175 Val Phe Asn Gly Ile Thr Leu Leu Ile Leu Ala Glu Leu Leu Ile Phe 180 185 190 Ser Val Pro Ile Val Tyr Glu Lys Tyr Lys Thr Gln Ile Asp His Tyr 195 200 205 Val Gly Ile Ala Arg Asp Gln Thr Lys Ser Ile Val Glu Lys Ile Gln 210 215 220 Ala Lys Leu Pro Gly Ile Ala Lys Lys Lys Ala Glu 225 230 235 27 1697 DNA human 27 cttcatcctg cccgccgtca ctgagaggat gttcaaccag aatgtggtgg cccagctctg 60 gtacttcgtg aagtgcatct acttcgccct gtccgcctac cagatccgct gcggctaccc 120 cacccgcatc ctcggcaact tcctcaccaa gaagtacaat catctcaacc tcttcctctt 180 ccaggggttc cggctggtgc cgttcctggt ggagctgcgg gcagtgatgg actgggtgtg 240 gacggacacc acgctgtccc tgtccagctg gatgtgtgtg gaggacatct atgccaacat 300 cttcatcatc aaatgcagcc gagagacaga gaagaaatac ccgcagccca aagggcagaa 360 gaagaagaag atcgtcaagt acggcatggg tggcctcatc atcctcttcc tcatcgccat 420 catctggttc ccgctgctct tcatgtcgct ggtgcgctcc gtggttgggg ttgtcaacca 480 gcccatcgat gtcaccgtca ccctgaagct gggcggctat gagccgctgt tcaccatgag 540 cgcccagcag ccgtccatca tccccttcac ggcccaggcc tatgaggagc tgtcccggca 600 gtttgacccc cagccgctgg ccatgcagtt catcagccag tacagccctg aggacgtcgt 660 cacggcgcag attgagggca gctccggggc gctgtggcgc atcagtcccc ccagccgtgc 720 ccagatgaag cgggagctct acaacggcac ggccgacatc accctgcgct tcacctggaa 780 cttccagagg gacctggcga agggaggcac tgtggagtat gccaacgaga agcacatgct 840 ggccctggcc cccaacagca ctgcacggcg gcagctggcc agcctgctcg agggcacctc 900 ggaccagtct gtggtcatcc ccaatctctt ccccaagtac atccgtgccc ccaacgggcc 960 cgaagccaac cctgtgaagc agctgcagcc caatgaggag gccgactacc tcggcgtgcg 1020 tatccagctg cggagggagc agggtgcggg ggccaccggc ttcctcgaat ggtgggtcat 1080 cgagctgcag gagtgccgga ccgactgcaa cctgctgccc atggtcattt tcagtgacaa 1140 ggtcagccca ccgagcctcg gcttcctggc tggctacggc atcatggggc tgtacgtgtc 1200 catcgtgctg gtcatcggca agttcgtgcg cggattcttc agcgagatct cgcactccat 1260 tatgttcgag gagctgccgt gcgtggaccg catcctcaag ctctgccagg acatcttcct 1320 ggtgcgggag actcgggagc tggagctgga ggaggagttg tacgccaagc tcatcttcct 1380 ctaccgctca ccggagacca tgatcaagtg gactcgtgag aaggagtagg agctgctgct 1440 ggcgcccgag agggaaggag ccggcctgct gggcagcgtg gccacaaggg gcggcactcc 1500 tcaggccggg ggagccactg ccccgtccaa ggccgccagc tgtgatgcat cctcccggcc 1560 tgcctgagcc ctgatgctgc tgtcagagaa ggacactgcg tccccacggc ctgcgtggcg 1620 ctgccgtccc ccacgtgtac tgtagagttt tttttttaat taaaaaatgt tttatttata 1680 caaaaaaaaa aaaaaaa 1697 28 466 PRT human 28 Met Phe Asn Gln Asn Val Val Ala Gln Leu Trp Tyr Phe Val Lys Cys 1 5 10 15 Ile Tyr Phe Ala Leu Ser Ala Tyr Gln Ile Arg Cys Gly Tyr Pro Thr 20 25 30 Arg Ile Leu Gly Asn Phe Leu Thr Lys Lys Tyr Asn His Leu Asn Leu 35 40 45 Phe Leu Phe Gln Gly Phe Arg Leu Val Pro Phe Leu Val Glu Leu Arg 50 55 60 Ala Val Met Asp Trp Val Trp Thr Asp Thr Thr Leu Ser Leu Ser Ser 65 70 75 80 Trp Met Cys Val Glu Asp Ile Tyr Ala Asn Ile Phe Ile Ile Lys Cys 85 90 95 Ser Arg Glu Thr Glu Lys Lys Tyr Pro Gln Pro Lys Gly Gln Lys Lys 100 105 110 Lys Lys Ile Val Lys Tyr Gly Met Gly Gly Leu Ile Ile Leu Phe Leu 115 120 125 Ile Ala Ile Ile Trp Phe Pro Leu Leu Phe Met Ser Leu Val Arg Ser 130 135 140 Val Val Gly Val Val Asn Gln Pro Ile Asp Val Thr Val Thr Leu Lys 145 150 155 160 Leu Gly Gly Tyr Glu Pro Leu Phe Thr Met Ser Ala Gln Gln Pro Ser 165 170 175 Ile Ile Pro Phe Thr Ala Gln Ala Tyr Glu Glu Leu Ser Arg Gln Phe 180 185 190 Asp Pro Gln Pro Leu Ala Met Gln Phe Ile Ser Gln Tyr Ser Pro Glu 195 200 205 Asp Val Val Thr Ala Gln Ile Glu Gly Ser Ser Gly Ala Leu Trp Arg 210 215 220 Ile Ser Pro Pro Ser Arg Ala Gln Met Lys Arg Glu Leu Tyr Asn Gly 225 230 235 240 Thr Ala Asp Ile Thr Leu Arg Phe Thr Trp Asn Phe Gln Arg Asp Leu 245 250 255 Ala Lys Gly Gly Thr Val Glu Tyr Ala Asn Glu Lys His Met Leu Ala 260 265 270 Leu Ala Pro Asn Ser Thr Ala Arg Arg Gln Leu Ala Ser Leu Leu Glu 275 280 285 Gly Thr Ser Asp Gln Ser Val Val Ile Pro Asn Leu Phe Pro Lys Tyr 290 295 300 Ile Arg Ala Pro Asn Gly Pro Glu Ala Asn Pro Val Lys Gln Leu Gln 305 310 315 320 Pro Asn Glu Glu Ala Asp Tyr Leu Gly Val Arg Ile Gln Leu Arg Arg 325 330 335 Glu Gln Gly Ala Gly Ala Thr Gly Phe Leu Glu Trp Trp Val Ile Glu 340 345 350 Leu Gln Glu Cys Arg Thr Asp Cys Asn Leu Leu Pro Met Val Ile Phe 355 360 365 Ser Asp Lys Val Ser Pro Pro Ser Leu Gly Phe Leu Ala Gly Tyr Gly 370 375 380 Ile Met Gly Leu Tyr Val Ser Ile Val Leu Val Ile Gly Lys Phe Val 385 390 395 400 Arg Gly Phe Phe Ser Glu Ile Ser His Ser Ile Met Phe Glu Glu Leu 405 410 415 Pro Cys Val Asp Arg Ile Leu Lys Leu Cys Gln Asp Ile Phe Leu Val 420 425 430 Arg Glu Thr Arg Glu Leu Glu Leu Glu Glu Glu Leu Tyr Ala Lys Leu 435 440 445 Ile Phe Leu Tyr Arg Ser Pro Glu Thr Met Ile Lys Trp Thr Arg Glu 450 455 460 Lys Glu 465 29 1333 DNA human 29 ggtgggtgca tcctgcgctg cggcgggcgc gctacccaga cgctggtgtg cagagccaca 60 tgaagcctgc tggggactgg gggccaggga gcagcaagcc agctgggact gaggcggacg 120 ctgtctcagg gagacgctga ctcgcaaaga cactcccttc cttgtgcctg ggtaaaaagt 180 ctcctcctgg ggtccctggc catcctgaat atccagaatg gtgtttctga agttcttctg 240 catgagtttc ttctgccacc tgtgtcaagg ctacttcgat ggccccctct acccagagat 300 gtccaatggg actctgcacc actacttcgt gcccgatggg gactatgagg agaacgatga 360 ccccgagaag tgccagctgc tcttcagggt gagtgaccac aggcgctgct cccaggggga 420 ggggagccag gttggcagcc tgctgagcct caccctgcgg gaggagttca ccgtgctggg 480 ccgccaggtg gaggatgctg ggcgcgtgct ggagggcatc agcaaaagca tctcctacga 540 cctagacggg gaagagagct atggcaagta cctgcggcgg gagtcccacc agatcgggga 600 tgcctactcc aactcggaca aatccctcac tgagctggag agcaagttca agcagggcca 660 ggaacaggac agccggcagg agagcaggct caacgaggac tttctgggaa tgctggtcca 720 caccaggtcc ctgctgaagg agacactgga catctctgtg gggctcaggg acaaatacga 780 gctgctggcc ctcaccatta ggagccatgg gacccgacta ggtcggctga aaaatgatta 840 tcttaaagta taggtggaag gatacaaatg ctagaaagag ggaatcaaat cagccccgtt 900 ttggagggtg ggggacagaa gatggggcta catttccccc atacctacta tttttttata 960 tcccgatttg cactttgaga atacatctaa ggtcatcttt caaaagagaa aaattggaca 1020 cttgagtgac tttgttttta gttttgtttt tgtacattat ttatgtgatt gttatggaat 1080 tgtcacctgg aaagaacaat tttaagcaat gtcatttcta gatgggtttc taattctgca 1140 gagacacccg tttcagccac atctaaaaga gcacagttta tgtggtgcgg aattaaactt 1200 ccccatcctg cagattatgt ggaaataccc aaagataata gtgcatagct cctttcagcc 1260 tctagccttc actcctgggc tccaaaagct atcccagttg cctgtttttc aaatgaggtt 1320 caaggtgctg ctt 1333 30 211 PRT human 30 Met Val Phe Leu Lys Phe Phe Cys Met Ser Phe Phe Cys His Leu Cys 1 5 10 15 Gln Gly Tyr Phe Asp Gly Pro Leu Tyr Pro Glu Met Ser Asn Gly Thr 20 25 30 Leu His His Tyr Phe Val Pro Asp Gly Asp Tyr Glu Glu Asn Asp Asp 35 40 45 Pro Glu Lys Cys Gln Leu Leu Phe Arg Val Ser Asp His Arg Arg Cys 50 55 60 Ser Gln Gly Glu Gly Ser Gln Val Gly Ser Leu Leu Ser Leu Thr Leu 65 70 75 80 Arg Glu Glu Phe Thr Val Leu Gly Arg Gln Val Glu Asp Ala Gly Arg 85 90 95 Val Leu Glu Gly Ile Ser Lys Ser Ile Ser Tyr Asp Leu Asp Gly Glu 100 105 110 Glu Ser Tyr Gly Lys Tyr Leu Arg Arg Glu Ser His Gln Ile Gly Asp 115 120 125 Ala Tyr Ser Asn Ser Asp Lys Ser Leu Thr Glu Leu Glu Ser Lys Phe 130 135 140 Lys Gln Gly Gln Glu Gln Asp Ser Arg Gln Glu Ser Arg Leu Asn Glu 145 150 155 160 Asp Phe Leu Gly Met Leu Val His Thr Arg Ser Leu Leu Lys Glu Thr 165 170 175 Leu Asp Ile Ser Val Gly Leu Arg Asp Lys Tyr Glu Leu Leu Ala Leu 180 185 190 Thr Ile Arg Ser His Gly Thr Arg Leu Gly Arg Leu Lys Asn Asp Tyr 195 200 205 Leu Lys Val 210 31 1102 DNA human 31 gtcttggggt ccctggctgg gtggccagac cccgaagcca gcgctgggaa gggctgcgga 60 tgcccgggtc agaggaaggg gcaggtccaa ggacacgcgg gtctggtcct gggcaagaac 120 cgccccctct ccgggcctgc ttcagtcttc ctttgcagaa caacgggcca ggccccttcc 180 ctctgccccc gggtgcttga agtctagccc catcctggtc caatgcgctc ttggtagcct 240 cctttcccag ctgcccgccc gccgccatgc cgcccttact gcccctgcgc ctgtgccggc 300 tgtggccccg caaccctccc tcccggctcc tcggagcggc cgccgggcag cggtccagac 360 ccagtactta ttatgaactg ttgggggtgc atcctggtgc cagcactgag gaagttaaac 420 gagctttctt ctccaagtcc aaagagctgc acccagaccg ggaccctggg aacccaagcc 480 tgcacagccg ctttgtggag ctgagcgagg cataccgtgt gctcagccgt gagcagagcc 540 gccgcagcta tgatgaccag ctccgctcag gtagtccccc aaagtctcca cgaaccacag 600 tccatgacaa gtctgcccac caaacacaca gctcctggac accccccaac gcacagtact 660 ggtcccagtt tcacagcgtg aggccacagg ggccccagtt gaggcagcag caacacaaac 720 aaaacaaaca agtgctgggg tactgcctcc tcctcatgct ggcgggcatg ggcctgcact 780 acattgcctt caggaaggtg aagcagatgc accttaactt catggatgaa aaggatcgga 840 tcatcacagc cttctacaac gaagcccggg cacgggccag ggccaacaga ggcatccttc 900 agcaggagcg acaacggcta gggcagcggc agccgccacc atccgagcca acccaaggcc 960 ccgagatcgt gccccggggc gccggcccct gaggggctca cctggatggg gcctgcagtg 1020 cgttcccgct ttgcttcctt ccctggacgg cccgctcccc gaaacgcgcg caataaagtg 1080 attcgcagaa aaaaaaaaaa aa 1102 32 241 PRT human 32 Met Pro Pro Leu Leu Pro Leu Arg Leu Cys Arg Leu Trp Pro Arg Asn 1 5 10 15 Pro Pro Ser Arg Leu Leu Gly Ala Ala Ala Gly Gln Arg Ser Arg Pro 20 25 30 Ser Thr Tyr Tyr Glu Leu Leu Gly Val His Pro Gly Ala Ser Thr Glu 35 40 45 Glu Val Lys Arg Ala Phe Phe Ser Lys Ser Lys Glu Leu His Pro Asp 50 55 60 Arg Asp Pro Gly Asn Pro Ser Leu His Ser Arg Phe Val Glu Leu Ser 65 70 75 80 Glu Ala Tyr Arg Val Leu Ser Arg Glu Gln Ser Arg Arg Ser Tyr Asp 85 90 95 Asp Gln Leu Arg Ser Gly Ser Pro Pro Lys Ser Pro Arg Thr Thr Val 100 105 110 His Asp Lys Ser Ala His Gln Thr His Ser Ser Trp Thr Pro Pro Asn 115 120 125 Ala Gln Tyr Trp Ser Gln Phe His Ser Val Arg Pro Gln Gly Pro Gln 130 135 140 Leu Arg Gln Gln Gln His Lys Gln Asn Lys Gln Val Leu Gly Tyr Cys 145 150 155 160 Leu Leu Leu Met Leu Ala Gly Met Gly Leu His Tyr Ile Ala Phe Arg 165 170 175 Lys Val Lys Gln Met His Leu Asn Phe Met Asp Glu Lys Asp Arg Ile 180 185 190 Ile Thr Ala Phe Tyr Asn Glu Ala Arg Ala Arg Ala Arg Ala Asn Arg 195 200 205 Gly Ile Leu Gln Gln Glu Arg Gln Arg Leu Gly Gln Arg Gln Pro Pro 210 215 220 Pro Ser Glu Pro Thr Gln Gly Pro Glu Ile Val Pro Arg Gly Ala Gly 225 230 235 240 Pro 33 966 DNA human 33 gagaagcatc gaggctatag gacgcagctg ttgccatgac ggcccagggg ggcctggtgg 60 ctaaccgagg ccggcgcttc aagtgggcca ttgagctaag cgggcctgga ggaggcagca 120 ggggtcgaag tgaccggggc agtggccagg gagactcgct ctacccagtc ggttacttgg 180 acaagcaagt gcctgatacc agcgtgcaag agacagaccg gatcctggtg gagaagcgct 240 gctgggacat cgccttgggt cccctcaaac agattcccat gaatctcttc atcatgtaca 300 tggcaggcaa tactatctcc atcttcccta ctatgatggt gtgtatgatg gcctggcgac 360 ccattcaggc acttatggcc atttcagcca ctttcaagat gttagaaagt tcaagccaga 420 agtttcttca gggtttggtc tatctcattg ggaacctgat gggtttggca ttggctgttt 480 acaagtgcca gtccatggga ctgttaccta cacatgcatc ggattggtta gccttcattg 540 agccccctga gagaatggag ttcagtggtg gaggactgct tttgtgaaca tgagaaagca 600 gcgcctggtc cctatgtatt tgggtcttat ttacatcctt ctttaagccc agtggctcct 660 cagcatactc ttaaactaat cacttatgtt aaaaagaacc aaaagactct tttctccatg 720 gtggggtgac aggtcctaga aggacaatgt gcatattacg acaaacacaa agaaactata 780 ccataaccca aggctgaaaa taatgtagaa aactttattt ttgtttccag tacagagcaa 840 aacaacaaca aaaaaacata actatgtaaa caagagaata actgctgcta aatcaagaac 900 tgttgcagca tctcctttca ataaattaaa tggttgagaa caatgcataa aaaaaaaaaa 960 aaaaaa 966 34 183 PRT human 34 Met Thr Ala Gln Gly Gly Leu Val Ala Asn Arg Gly Arg Arg Phe Lys 1 5 10 15 Trp Ala Ile Glu Leu Ser Gly Pro Gly Gly Gly Ser Arg Gly Arg Ser 20 25 30 Asp Arg Gly Ser Gly Gln Gly Asp Ser Leu Tyr Pro Val Gly Tyr Leu 35 40 45 Asp Lys Gln Val Pro Asp Thr Ser Val Gln Glu Thr Asp Arg Ile Leu 50 55 60 Val Glu Lys Arg Cys Trp Asp Ile Ala Leu Gly Pro Leu Lys Gln Ile 65 70 75 80 Pro Met Asn Leu Phe Ile Met Tyr Met Ala Gly Asn Thr Ile Ser Ile 85 90 95 Phe Pro Thr Met Met Val Cys Met Met Ala Trp Arg Pro Ile Gln Ala 100 105 110 Leu Met Ala Ile Ser Ala Thr Phe Lys Met Leu Glu Ser Ser Ser Gln 115 120 125 Lys Phe Leu Gln Gly Leu Val Tyr Leu Ile Gly Asn Leu Met Gly Leu 130 135 140 Ala Leu Ala Val Tyr Lys Cys Gln Ser Met Gly Leu Leu Pro Thr His 145 150 155 160 Ala Ser Asp Trp Leu Ala Phe Ile Glu Pro Pro Glu Arg Met Glu Phe 165 170 175 Ser Gly Gly Gly Leu Leu Leu 180 35 1570 DNA human 35 gggccgggcg cggcgcagag gcgggcgcct accagccggc agctccggag ctgcccgcgc 60 catgtccgcg cacaatcggg gcaccgagct cgaccttagc tggatctcca aaatacaagt 120 gaatcacccg gcagttctga ggcgtgcgga acaaatccag gctcgcagaa ccgtgaaaaa 180 ggagtggcag gctgcttggc tcctgaaagc tgttaccttt atagatctta ctacactttc 240 aggtgatgat acatcttcca acattcaaag gctctgttat aaagccaaat acccaatccg 300 ggaagatctc ttaaaagctt taaatatgca tgataaaggc attactacag ccgccgtttg 360 tgtttatccc gcccgggtgt gtgatgctgt aaaagcactc aaggctgcag gctgtaatat 420 ccctgtggca tcagtggccg ctggatttcc agctggacag actcatttga agacacgatt 480 agaagagatc agattggctg tggaagatgg agctacagaa atcgacgtgg taattaacag 540 aagcttggtg ctgacaggcc agtgggaagc cctgtacgat gagattcgtc agtttcgcaa 600 ggcctgtggg gaggctcatc ttaaaactat attagcgaca ggagaacttg gaactcttac 660 taatgtctat aaagccagta tgatagcaat gatggcagga tcagatttta ttaagacctc 720 tactggaaaa gaaacagtaa atgccacctt cccggtagct atagtaatgc tgcgggccat 780 tagagatttc ttctggaaaa ctggaaacaa gatagggttt aaaccagcag gaggcatccg 840 cagtgcaaag gattcccttg cttggctctc tcttgtaaag gaggagcttg gagatgagtg 900 gctgaagcca gaactctttc gaataggtgc cagtactctg ctctcggaca ttgagaggca 960 gatttaccat catgtgactg gaagatatgc agcttatcat gatcttccaa tgtcttaaat 1020 cagtcaccag ttccagaaaa gttctttacg acaatgttta aaaattattt ttctacgtaa 1080 ttgctaaaat tatttaatta aaaaattggg cagtaggtaa ctggcattcc tctctttaaa 1140 atttctaccg aacttaatgg aatggaaaaa gcaaactcat ccacatgtgg tactcatttc 1200 aggcacatct gaaatgatct taattactag aagatctgca ctattaactt tgtgaagagt 1260 ttctcctaaa aactttaagt aaaatgttaa tggtagcttt gataacatca aattctaagg 1320 gagaaaaaaa caatattaaa ccgcccaagc agtgtgccct agcagaggaa aatgcaacat 1380 ctcgcaagcg ctgctgtaac gacttcagga gtcactgatt cagcactaat ttcctgctgt 1440 gaaaactcat ctttcatttt tgccgtggat aggcgctttt attaattgtt gtcctaatga 1500 aatttctgac attgtcatat acaacgatga atatcattaa aatttttaaa ataaaaaaaa 1560 aaaaaaaaaa 1570 36 318 PRT human 36 Met Ser Ala His Asn Arg Gly Thr Glu Leu Asp Leu Ser Trp Ile Ser 1 5 10 15 Lys Ile Gln Val Asn His Pro Ala Val Leu Arg Arg Ala Glu Gln Ile 20 25 30 Gln Ala Arg Arg Thr Val Lys Lys Glu Trp Gln Ala Ala Trp Leu Leu 35 40 45 Lys Ala Val Thr Phe Ile Asp Leu Thr Thr Leu Ser Gly Asp Asp Thr 50 55 60 Ser Ser Asn Ile Gln Arg Leu Cys Tyr Lys Ala Lys Tyr Pro Ile Arg 65 70 75 80 Glu Asp Leu Leu Lys Ala Leu Asn Met His Asp Lys Gly Ile Thr Thr 85 90 95 Ala Ala Val Cys Val Tyr Pro Ala Arg Val Cys Asp Ala Val Lys Ala 100 105 110 Leu Lys Ala Ala Gly Cys Asn Ile Pro Val Ala Ser Val Ala Ala Gly 115 120 125 Phe Pro Ala Gly Gln Thr His Leu Lys Thr Arg Leu Glu Glu Ile Arg 130 135 140 Leu Ala Val Glu Asp Gly Ala Thr Glu Ile Asp Val Val Ile Asn Arg 145 150 155 160 Ser Leu Val Leu Thr Gly Gln Trp Glu Ala Leu Tyr Asp Glu Ile Arg 165 170 175 Gln Phe Arg Lys Ala Cys Gly Glu Ala His Leu Lys Thr Ile Leu Ala 180 185 190 Thr Gly Glu Leu Gly Thr Leu Thr Asn Val Tyr Lys Ala Ser Met Ile 195 200 205 Ala Met Met Ala Gly Ser Asp Phe Ile Lys Thr Ser Thr Gly Lys Glu 210 215 220 Thr Val Asn Ala Thr Phe Pro Val Ala Ile Val Met Leu Arg Ala Ile 225 230 235 240 Arg Asp Phe Phe Trp Lys Thr Gly Asn Lys Ile Gly Phe Lys Pro Ala 245 250 255 Gly Gly Ile Arg Ser Ala Lys Asp Ser Leu Ala Trp Leu Ser Leu Val 260 265 270 Lys Glu Glu Leu Gly Asp Glu Trp Leu Lys Pro Glu Leu Phe Arg Ile 275 280 285 Gly Ala Ser Thr Leu Leu Ser Asp Ile Glu Arg Gln Ile Tyr His His 290 295 300 Val Thr Gly Arg Tyr Ala Ala Tyr His Asp Leu Pro Met Ser 305 310 315 37 1542 DNA human 37 ccaacttcca actccctgtc ctgtcctagg taacccctcc accccgccat tctcctatcc 60 cgtgtctgtc cccatccctg tgacccctga cccctggcct ttgccactcc ccagggaccg 120 atgatgtggc gaccatcagt tctgctgctt ctgttgctac tgaggcacgg ggcccagggg 180 aagccatccc cagacgcagg ccctcatggc caggggaggg tgcaccaggc ggcccccctg 240 agcgacgctc cccatgatga cgcccacggg aacttccagt acgaccatga ggctttcctg 300 ggacgggaag tggccaagga attcgaccaa ctcaccccag aggaaagcca ggcccgtctg 360 gggcggatcg tggaccgcat ggaccgcgcg ggggacggcg acggctgggt gtcgctggcc 420 gagcttcgcg cgtggatcgc gcacacgcag cagcggcaca tacgggactc ggtgagcgcg 480 gcctgggaca cgtacgacac ggaccgcgac gggcgtgtgg gttgggagga gctgcgcaac 540 gccacctatg gccactacgc gcccggtgaa gaatttcatg acgtggagga tgcagagacc 600 tacaaaaaga tgctggctcg ggacgagcgg cgtttccggg tggccgacca ggatggggac 660 tcgatggcca ctcgagagga gctgacagcc ttcctgcacc ccgaggagtt ccctcacatg 720 cgggacatcg tgattgctga aaccctggag gacctggaca gaaacaaaga tggctatgtc 780 caggtggagg agtacatcgc ggatctgtac tcagccgagc ctggggagga ggagccggcg 840 tgggtgcaga cggagaggca gcagttccgg gacttccggg atctgaacaa ggatgggcac 900 ctggatggga gtgaggtggg ccactgggtg ctgccccctg cccaggacca gcccctggtg 960 gaagccaacc acctgctgca cgagagcgac acggacaagg atgggcggct gagcaaagcg 1020 gaaatcctgg gtaattggaa catgtttgtg ggcagtcagg ccaccaacta tggcgaggac 1080 ctgacccggc accacgatga gctgtgagca ccgcgcacct gccacagcct cagaggcccg 1140 cacaatgacc ggaggagggg ccgctgtggt ctggccccct ccctgtccag gccccgcagg 1200 aggcagatgc agtcccaggc atcctcctgc ccctgggctc tcagggaccc cctgggtcgg 1260 cttctgtccc tgtcacaccc ccaaccccag ggaggggctg tcatagtccc agaggataag 1320 caatacctat ttctgactga gtctcccagc ccagacccag ggacccttgg ccccaagctc 1380 agctctaaga accgccccaa cccctccagc tccaaatctg agcctccacc acatagactg 1440 aaactcccct ggccccagcc ctctcctgcc tggcctggcc tgggacacct cctctctgcc 1500 aggaggcaat aaaagccagc gccgggaaaa aaaaaaaaaa aa 1542 38 328 PRT 38 38 Met Met Trp Arg Pro Ser Val Leu Leu Leu Leu Leu Leu Leu Arg His 1 5 10 15 Gly Ala Gln Gly Lys Pro Ser Pro Asp Ala Gly Pro His Gly Gln Gly 20 25 30 Arg Val His Gln Ala Ala Pro Leu Ser Asp Ala Pro His Asp Asp Ala 35 40 45 His Gly Asn Phe Gln Tyr Asp His Glu Ala Phe Leu Gly Arg Glu Val 50 55 60 Ala Lys Glu Phe Asp Gln Leu Thr Pro Glu Glu Ser Gln Ala Arg Leu 65 70 75 80 Gly Arg Ile Val Asp Arg Met Asp Arg Ala Gly Asp Gly Asp Gly Trp 85 90 95 Val Ser Leu Ala Glu Leu Arg Ala Trp Ile Ala His Thr Gln Gln Arg 100 105 110 His Ile Arg Asp Ser Val Ser Ala Ala Trp Asp Thr Tyr Asp Thr Asp 115 120 125 Arg Asp Gly Arg Val Gly Trp Glu Glu Leu Arg Asn Ala Thr Tyr Gly 130 135 140 His Tyr Ala Pro Gly Glu Glu Phe His Asp Val Glu Asp Ala Glu Thr 145 150 155 160 Tyr Lys Lys Met Leu Ala Arg Asp Glu Arg Arg Phe Arg Val Ala Asp 165 170 175 Gln Asp Gly Asp Ser Met Ala Thr Arg Glu Glu Leu Thr Ala Phe Leu 180 185 190 His Pro Glu Glu Phe Pro His Met Arg Asp Ile Val Ile Ala Glu Thr 195 200 205 Leu Glu Asp Leu Asp Arg Asn Lys Asp Gly Tyr Val Gln Val Glu Glu 210 215 220 Tyr Ile Ala Asp Leu Tyr Ser Ala Glu Pro Gly Glu Glu Glu Pro Ala 225 230 235 240 Trp Val Gln Thr Glu Arg Gln Gln Phe Arg Asp Phe Arg Asp Leu Asn 245 250 255 Lys Asp Gly His Leu Asp Gly Ser Glu Val Gly His Trp Val Leu Pro 260 265 270 Pro Ala Gln Asp Gln Pro Leu Val Glu Ala Asn His Leu Leu His Glu 275 280 285 Ser Asp Thr Asp Lys Asp Gly Arg Leu Ser Lys Ala Glu Ile Leu Gly 290 295 300 Asn Trp Asn Met Phe Val Gly Ser Gln Ala Thr Asn Tyr Gly Glu Asp 305 310 315 320 Leu Thr Arg His His Asp Glu Leu 325 39 1990 DNA human 39 cacgagcctg cccggccccc ggctccagcg agcgagcggc gagcaggcgg ctcacagagg 60 cctggccgcc cacggaaccc ggggcccggc ggccgccgcc gcgatgtttc cccgcgagaa 120 gacgtggaac atctcgttcg cgggctgcgg cttcctcggc gtctactacg tcggcgtggc 180 ctcctgcctc cgcgagcacg cgcccttcct ggtggccaac gccacgcaca tctacggcgc 240 ctcggccggg gcgctcacgg ccacggcgct ggtcaccggg gtctgcctgg gtgaggctgg 300 tgccaagttc attgaggtat ctaaagaggc ccggaagcgg ttcctgggcc ccctgcaccc 360 ctccttcaac ctggtaaaga tcatccgcag tttcctgctg aaggtcctgc ctgctgatag 420 ccatgagcat gccagtgggc gcctgggcat ctccctgacc cgcgtgtcag acggcgagaa 480 tgtcattata tcccacttca actccaagga cgagctcatc caggccaatg tctgcagcgg 540 tttcatcccc gtgtactgtg ggctcatccc tccctccctc cagggggtgc gctacgtgga 600 tggtggcatt tcagacaacc tgccactcta tgagcttaag aacaccatca cagtgtcccc 660 cttctcgggc gagagtgaca tctgtccgca ggacagctcc accaacatcc acgagctgcg 720 ggtcaccaac accagcatcc agttcaacct gcgcaacctc taccgcctct ccaaggccct 780 cttcccgccg gagcccctgg tgctgcgaga gatgtgcaag cagggatacc gggatggcct 840 gcgctttctg cagcggaacg gcctcctgaa ccggcccaac cccttgctgg cgttgccccc 900 cgcccgcccc cacggcccag aggacaagga ccaggcagtg gagagcgccc aagcggagga 960 ttactcgcag ctgcccggag aagatcacat cctggagcac ctgcccgccc ggctcaatga 1020 ggccctgctg gaggcctgcg tggagcccac ggacctgctg accaccctct ccaacatgct 1080 gcctgtgcgt ctggccacgg ccatgatggt gccctacacg ctgccgctgg agagcgctct 1140 gtccttcacc atccgcttgc tggagtggct gcccgacgtt cccgaggaca tccggtggat 1200 gaaggagcag acgggcagca tctgccagta cctggtgatg cgcgccaaga ggaagctggg 1260 caggcacctg ccctccaggc tgccggagca ggtggagctg cgccgcgtcc agtcgctgcc 1320 gtccgtgccg ctgtcctgcg ccgcctacag agaggcactg cccggctgga tgcgcaacaa 1380 cctctcgctg ggggacgcgc tggccaagtg ggaggagtgc cagcgccagc tgctgctcgg 1440 cctcttctgc accaacgtgg ccttcccgcc cgaagctctg cgcatgcgcg cacccgccga 1500 cccggctccc gcccccgcgg acccagcatc cccgcagcac cagccggccg ggcctgcccc 1560 cttgctgagc acccctgctc ccgaggcccg gcccgtgatc ggggccctgg ggctgtgaga 1620 ccccgaccct ctcgaggaac cctgcctgag acgcctccat taccactgcg cagtgagatg 1680 aggggactca cagttgccaa gaggggtctt tgccgtgggc cccctcgcca gccactcacc 1740 agctgcactg agaggggagg tttccacacc cctcccctgg gccgctgagg ccccgcgcac 1800 ctgtgcctta atcttccctc ccctgtgctg cccgagcacc tcccccgccc ctttactcct 1860 gggaactttg cagctgccct tccctccccg tttttcatgg cctgctgaaa tatgtgtgtg 1920 aagaattatt tattttcgcc aaagcacatg taataaatgc tgcagcccag aaaaaaaaaa 1980 aaaaaaaaaa 1990 40 504 PRT human 40 Met Phe Pro Arg Glu Lys Thr Trp Asn Ile Ser Phe Ala Gly Cys Gly 1 5 10 15 Phe Leu Gly Val Tyr Tyr Val Gly Val Ala Ser Cys Leu Arg Glu His 20 25 30 Ala Pro Phe Leu Val Ala Asn Ala Thr His Ile Tyr Gly Ala Ser Ala 35 40 45 Gly Ala Leu Thr Ala Thr Ala Leu Val Thr Gly Val Cys Leu Gly Glu 50 55 60 Ala Gly Ala Lys Phe Ile Glu Val Ser Lys Glu Ala Arg Lys Arg Phe 65 70 75 80 Leu Gly Pro Leu His Pro Ser Phe Asn Leu Val Lys Ile Ile Arg Ser 85 90 95 Phe Leu Leu Lys Val Leu Pro Ala Asp Ser His Glu His Ala Ser Gly 100 105 110 Arg Leu Gly Ile Ser Leu Thr Arg Val Ser Asp Gly Glu Asn Val Ile 115 120 125 Ile Ser His Phe Asn Ser Lys Asp Glu Leu Ile Gln Ala Asn Val Cys 130 135 140 Ser Gly Phe Ile Pro Val Tyr Cys Gly Leu Ile Pro Pro Ser Leu Gln 145 150 155 160 Gly Val Arg Tyr Val Asp Gly Gly Ile Ser Asp Asn Leu Pro Leu Tyr 165 170 175 Glu Leu Lys Asn Thr Ile Thr Val Ser Pro Phe Ser Gly Glu Ser Asp 180 185 190 Ile Cys Pro Gln Asp Ser Ser Thr Asn Ile His Glu Leu Arg Val Thr 195 200 205 Asn Thr Ser Ile Gln Phe Asn Leu Arg Asn Leu Tyr Arg Leu Ser Lys 210 215 220 Ala Leu Phe Pro Pro Glu Pro Leu Val Leu Arg Glu Met Cys Lys Gln 225 230 235 240 Gly Tyr Arg Asp Gly Leu Arg Phe Leu Gln Arg Asn Gly Leu Leu Asn 245 250 255 Arg Pro Asn Pro Leu Leu Ala Leu Pro Pro Ala Arg Pro His Gly Pro 260 265 270 Glu Asp Lys Asp Gln Ala Val Glu Ser Ala Gln Ala Glu Asp Tyr Ser 275 280 285 Gln Leu Pro Gly Glu Asp His Ile Leu Glu His Leu Pro Ala Arg Leu 290 295 300 Asn Glu Ala Leu Leu Glu Ala Cys Val Glu Pro Thr Asp Leu Leu Thr 305 310 315 320 Thr Leu Ser Asn Met Leu Pro Val Arg Leu Ala Thr Ala Met Met Val 325 330 335 Pro Tyr Thr Leu Pro Leu Glu Ser Ala Leu Ser Phe Thr Ile Arg Leu 340 345 350 Leu Glu Trp Leu Pro Asp Val Pro Glu Asp Ile Arg Trp Met Lys Glu 355 360 365 Gln Thr Gly Ser Ile Cys Gln Tyr Leu Val Met Arg Ala Lys Arg Lys 370 375 380 Leu Gly Arg His Leu Pro Ser Arg Leu Pro Glu Gln Val Glu Leu Arg 385 390 395 400 Arg Val Gln Ser Leu Pro Ser Val Pro Leu Ser Cys Ala Ala Tyr Arg 405 410 415 Glu Ala Leu Pro Gly Trp Met Arg Asn Asn Leu Ser Leu Gly Asp Ala 420 425 430 Leu Ala Lys Trp Glu Glu Cys Gln Arg Gln Leu Leu Leu Gly Leu Phe 435 440 445 Cys Thr Asn Val Ala Phe Pro Pro Glu Ala Leu Arg Met Arg Ala Pro 450 455 460 Ala Asp Pro Ala Pro Ala Pro Ala Asp Pro Ala Ser Pro Gln His Gln 465 470 475 480 Pro Ala Gly Pro Ala Pro Leu Leu Ser Thr Pro Ala Pro Glu Ala Arg 485 490 495 Pro Val Ile Gly Ala Leu Gly Leu 500 41 684 DNA human 41 accgtcatgc tccagttctt tgtgcacttc ctgagccttg tctacctgta ccgtgaggcc 60 caggcccgga gccccgagaa gcaggagcag ttcgtggact tgtacaagga gtttgagcca 120 agcctggtca acagcaccgt ctacatcatg gccatggcca tgcagatggc caccttcgcc 180 atcaattaca aaggcccgcc cttcatggag agcctgcccg agaacaagcc cctggtgtgg 240 agtctggcag tttcactcct ggccatcatt ggcctgctcc tcggctcctc gcccgacttc 300 aacagccagt ttggcctcgt ggacatccct gtggagttca agctggtcat tgcccaggtc 360 ctgctcctgg acttctgcct ggcgctcctg gccgaccgcg tcctgcagtt cttcctgggg 420 accccgaagc tgaaagtgcc ttcctgagat ggcagtgctg gtacccactg cccaccctgg 480 ctgccgctgg gcgggaaccc caacagggcc ccgggaggga accctgcccc caacccccca 540 cagcaaggct gtacagtctc gcccttggaa gactgagctg ggacccccac agccatccgc 600 tggcttggcc agcagaacca gccccaagcc agcacctttg gtaaataaag cagcatctga 660 gattttaaaa aaaaaaaaaa aaaa 684 42 146 PRT human 42 Met Leu Gln Phe Phe Val His Phe Leu Ser Leu Val Tyr Leu Tyr Arg 1 5 10 15 Glu Ala Gln Ala Arg Ser Pro Glu Lys Gln Glu Gln Phe Val Asp Leu 20 25 30 Tyr Lys Glu Phe Glu Pro Ser Leu Val Asn Ser Thr Val Tyr Ile Met 35 40 45 Ala Met Ala Met Gln Met Ala Thr Phe Ala Ile Asn Tyr Lys Gly Pro 50 55 60 Pro Phe Met Glu Ser Leu Pro Glu Asn Lys Pro Leu Val Trp Ser Leu 65 70 75 80 Ala Val Ser Leu Leu Ala Ile Ile Gly Leu Leu Leu Gly Ser Ser Pro 85 90 95 Asp Phe Asn Ser Gln Phe Gly Leu Val Asp Ile Pro Val Glu Phe Lys 100 105 110 Leu Val Ile Ala Gln Val Leu Leu Leu Asp Phe Cys Leu Ala Leu Leu 115 120 125 Ala Asp Arg Val Leu Gln Phe Phe Leu Gly Thr Pro Lys Leu Lys Val 130 135 140 Pro Ser 145 43 1152 DNA human 43 ggcacgaggg cagcctcccc tcgctcgctc tcctcttcct ctagggcccc agcgcagctc 60 gggagcccgc gcaccgaggc gctaggggca ccgcgcacta gagggacacc cgccgcgcct 120 ggacagcccc cggcgggcgc ccccctcgca cctcctgccc cgcgcgggcc gcgctcccct 180 cccccgcgcc tgtgtcccca gggcgcaggg ccgcgcgtcc agccccagac ccgccggggt 240 ccctggggac gcgccagccc ggcagtggct cgacgatgga ggagccgcag cgcgcccgct 300 cgcacacagt caccaccacc gccagctcct tcgcagagaa cttctccacc agcagcagca 360 gcttcgccta cgaccgggag ttcctccgca ccctgcccgg cttcctcatc gtggccgaga 420 tcgttctggg gctgctggta tggacgctta ttgctggaac tgagtacttc cgggtccccg 480 catttggctg ggtcatgttt gtagctgtat tttactgggt cctcaccgtc ttcttcctca 540 ttatctacat aacaatgacc tacaccagga ttccccaggt gccctggaca acagtgggcc 600 tgtgctttaa cggcagtgcc ttcgtcttgt acctctctgc cgctgttgta gatgcatctt 660 ccgtctcccc tgagagggac agtcacaact tcaacagctg ggcggcctca tcgttctttg 720 ccttcctggt caccatctgc tacgctggaa atacatattt cagttttata gcatggagat 780 ccaggaccat acagtgattt accattttga taattaaaag gaaaaaaaaa ggaagactct 840 cactgtaaaa acagctgtag gtataatgta tattcccaga gaattgtatt taactaatta 900 atgtttttta tattcttaaa tttgctcaca aattgtggtt tgttacaatt aaactggata 960 cttatttgca aagtgttgta gcttataatg aactcttaag tatcttatta atgtattaat 1020 gtcttcatag atcatatttt cttagacaat gtttaaatag ataaattgct aatattgaga 1080 atgtgtcaag tttgtaaacc taacttttaa gatgccagat tcttttttga ttaaatgttg 1140 caaaatccca aa 1152 44 173 PRT human 44 Met Glu Glu Pro Gln Arg Ala Arg Ser His Thr Val Thr Thr Thr Ala 1 5 10 15 Ser Ser Phe Ala Glu Asn Phe Ser Thr Ser Ser Ser Ser Phe Ala Tyr 20 25 30 Asp Arg Glu Phe Leu Arg Thr Leu Pro Gly Phe Leu Ile Val Ala Glu 35 40 45 Ile Val Leu Gly Leu Leu Val Trp Thr Leu Ile Ala Gly Thr Glu Tyr 50 55 60 Phe Arg Val Pro Ala Phe Gly Trp Val Met Phe Val Ala Val Phe Tyr 65 70 75 80 Trp Val Leu Thr Val Phe Phe Leu Ile Ile Tyr Ile Thr Met Thr Tyr 85 90 95 Thr Arg Ile Pro Gln Val Pro Trp Thr Thr Val Gly Leu Cys Phe Asn 100 105 110 Gly Ser Ala Phe Val Leu Tyr Leu Ser Ala Ala Val Val Asp Ala Ser 115 120 125 Ser Val Ser Pro Glu Arg Asp Ser His Asn Phe Asn Ser Trp Ala Ala 130 135 140 Ser Ser Phe Phe Ala Phe Leu Val Thr Ile Cys Tyr Ala Gly Asn Thr 145 150 155 160 Tyr Phe Ser Phe Ile Ala Trp Arg Ser Arg Thr Ile Gln 165 170 45 6 DNA human 45 aataaa 6 46 6 DNA human 46 attaaa 6 

We claim:
 1. An isolated and purified protein comprising an amino acid sequence which is at least 85% identical to an amino acid sequence selected from the group consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and 44, wherein percent identity is determined using a Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of
 1. 2. The isolated and purified protein of claim 1 wherein the amino acid sequence comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and
 44. 3. An isolated and purified protein comprising an amino acid sequence selected from the group consisting of at least 95 contiguous amino acids of SEQ ID NO:2, at least 101 contiguous amino acids of SEQ ID NO:4, at least 14 contiguous amino acids selected from amino acids 1-312 of SEQ ID NO:6, at least 179 contiguous amino acids of SEQ ID NO:6, at least 75 contiguous amino acids of SEQ ID NO:6, at least 179 contiguous amino acids of SEQ ID NO:8, at least 136 contiguous amino acids of SEQ ID NO:8, at least 17 contiguous amino acids selected from amino acids 1-287 of SEQ ID NO:8, at least 82 contiguous amino acids of SEQ ID NO:10, at least 31 contiguous amino acids selected from amino acids 1-238 of SEQ ID NO:10, at least 96 contiguous amino acids of SEQ ID NO:12, at least 27 contiguous amino acids selected from amino acids 250-383 of SEQ ID NO:12, at least 6 contiguous amino acids selected from amino acids 1-184 of SEQ ID NO:12, at least 8 contiguous amino acids selected from amino acids 268-364 of SEQ ID NO:12, at least 104 contiguous amino acids of SEQ ID NO:14, at least 75 contiguous amino acids of SEQ ID NO:14, at least 17 contiguous amino acids selected from amino acids 1-150 of SEQ ID NO:14, at least 6 contiguous amino acids selected from amino acids 204-261 of SEQ ID NO:14, at least 6 contiguous amino acids selected from amino acids 1-111 of SEQ ID NO:14, at least 8 contiguous amino acids of SEQ ID NO:16, at least 46 contiguous amino acids of SEQ ID NO:18, at least 39 contiguous amino acids selected from amino acids 13-232 of SEQ ID NO:18, at least 6 contiguous amino acids of SEQ ID NO:20, at least 7 contiguous amino acids of SEQ ID NO:22, at least 7 contiguous amino acids of SEQ ID NO:24, at least 11 contiguous amino acids of SEQ ID NO:26, at least 257 contiguous amino acids of SEQ ID NO:28, at least 6 contiguous amino acids selected from amino acids 1-31 of SEQ ID NO:28, at least 6 contiguous amino acids of SEQ ID NO:30, at least 117 contiguous amino acids of SEQ ID NO:32, at least 6 contiguous amino acids selected from amino acids 1-65 of SEQ ID NO:32, at least 6 contiguous amino acids of SEQ ID NO:34, at least 14 contiguous amino acids of SEQ ID NO:36, at least 19 contiguous amino acids of SEQ ID NO:38, at least 8 contiguous amino acids of SEQ ID NO:40, at least 7 contiguous amino acids of SEQ ID NO:42, and at least 10 contiguous amino acids of SEQ ID NO:44.
 4. A fusion protein comprising two protein segments joined together with a peptide bond, wherein the first protein segment consists of an amino acid sequence selected from the group consisting of at least 95 contiguous amino acids of SEQ ID NO:2, at least 101 contiguous amino acids of SEQ ID NO:4, at least 14 contiguous amino acids selected from amino acids 1-312 of SEQ ID NO:6, at least 179 contiguous amino acids of SEQ ID NO:6, at least 75 contiguous amino acids of SEQ ID NO:6, at least 179 contiguous amino acids of SEQ ID NO:8, at least 136 contiguous amino acids of SEQ ID NO:8, at least 17 contiguous amino acids selected from amino acids 1-287 of SEQ ID NO:8, at least 82 contiguous amino acids of SEQ ID NO:10, at least 31 contiguous amino acids selected from amino acids 1-238 of SEQ ID NO:10, at least 96 contiguous amino acids of SEQ ID NO:12, at least 27 contiguous amino acids selected from amino acids 250-383 of SEQ ID NO:12, at least 6 contiguous amino acids selected from amino acids 1-184 of SEQ ID NO:12, at least 8 contiguous amino acids selected from amino acids 268-364 of SEQ ID NO:12, at least 104 contiguous amino acids of SEQ ID NO:14, at least 75 contiguous amino acids of SEQ ID NO:14, at least 17 contiguous amino acids selected from amino acids 1-150 of SEQ ID NO:14, at least 6 contiguous amino acids selected from amino acids 204-261 of SEQ ID NO:14, at least 6 contiguous amino acids selected from amino acids 1-111 of SEQ ID NO:14, at least 8 contiguous amino acids of SEQ ID NO:16, at least 46 contiguous amino acids of SEQ ID NO:18, at least 39 contiguous amino acids selected from amino acids 13-232 of SEQ ID NO:18, at least 6 contiguous amino acids of SEQ ID NO:20, at least 7 contiguous amino acids of SEQ ID NO:22, at least 7 contiguous amino acids of SEQ ID NO:24, at least 11 contiguous amino acids of SEQ ID NO:26, at least 257 contiguous amino acids of SEQ ID NO:28, at least 6 contiguous amino acids selected from amino acids 1-31 of SEQ ID NO:28, at least 6 contiguous amino acids of SEQ ID NO:30, at least 117 contiguous amino acids of SEQ ID NO:32, at least 6 contiguous amino acids selected from amino acids 1-65 of SEQ ID NO:32, at least 6 contiguous amino acids of SEQ ID NO:34, at least 14 contiguous amino acids of SEQ ID NO:36, at least 19 contiguous amino acids of SEQ ID NO:38, at least 8 contiguous amino acids of SEQ ID NO:40, at least 7 contiguous amino acids of SEQ ID NO:42, and at least 10 contiguous amino acids of SEQ ID NO:44.
 5. A preparation of antibodies which specifically binds to a protein comprising an amino acid sequence selected from the group consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and
 44. 6. An isolated and purified subgenomic polynucleotide which encodes a protein comprising an amino acid sequence which is at least 85% identical to an amino acid sequence selected from the group consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and 44, wherein percent identity is determined using a Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of
 1. 7. The isolated and purified subgenomic polynucleotide of claim 6 wherein the amino acid sequence is selected from the group consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and
 44. 8. An isolated and purified subgenomic polynucleotide comprising a nucleotide sequence which is at least 85% identical to a nucleotide sequence selected from the group consisting of SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 31, 33, 35, 37, 39, 41, 43, 45, and the complements thereof, wherein percent identity is determined using a Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of
 1. 9. An isolated and purified subgenomic polynucleotide which encodes an amino acid sequence selected from the group consisting of at least 95 contiguous amino acids of SEQ ID NO:2, at least 101 contiguous amino acids of SEQ ID NO:4, at least 14 contiguous amino acids selected from amino acids 1-312 of SEQ ID NO:6, at least 179 contiguous amino acids of SEQ ID NO:6, at least 75 contiguous amino acids of SEQ ID NO:6, at least 179 contiguous amino acids of SEQ ID NO:8, at least 136 contiguous amino acids of SEQ ID NO:8, at least 17 contiguous amino acids selected from amino acids 1-287 of SEQ ID NO:8, at least 82 contiguous amino acids of SEQ ID NO:10, at least 31 contiguous amino acids selected from amino acids 1-238 of SEQ ID NO:10, at least 96 contiguous amino acids of SEQ ID NO:12, at least 27 contiguous amino acids selected from amino acids 250-383 of SEQ ID NO:12, at least 6 contiguous amino acids selected from amino acids 1-184 of SEQ ID NO:12, at least 8 contiguous amino acids selected from amino acids 268-364 of SEQ ID NO:12, at least 104 contiguous amino acids of SEQ ID NO:14, at least 75 contiguous amino acids of SEQ ID NO:14, at least 17 contiguous amino acids selected from amino acids 1-150 of SEQ ID NO:14, at least 6 contiguous amino acids selected from amino acids 204-261 of SEQ ID NO:14, at least 6 contiguous amino acids selected from amino acids 1 -11 of SEQ ID NO:14, at least 8 contiguous amino acids of SEQ ID NO:16, at least 46 contiguous amino acids of SEQ ID NO:18, at least 39 contiguous amino acids selected from amino acids 13-232 of SEQ ID NO:18, at least 6 contiguous amino acids of SEQ ID NO:20, at least 7 contiguous amino acids of SEQ ID NO:22, at least 7 contiguous amino acids of SEQ ID NO:24, at least 11 contiguous amino acids of SEQ ID NO:26, at least 257 contiguous amino acids of SEQ ID NO:28, at least 6 contiguous amino acids selected from amino acids 1-31 of SEQ ID NO:28, at least 6 contiguous amino acids of SEQ ID NO:30, at least 117 contiguous amino acids of SEQ ID NO:32, at least 6 contiguous amino acids selected from amino acids 1-65 of SEQ ID NO:32, at least 6 contiguous amino acids of SEQ ID NO:34, at least 14 contiguous amino acids of SEQ ID NO:36, at least 19 contiguous amino acids of SEQ ID NO:38, at least 8 contiguous amino acids of SEQ ID NO:40, at least 7 contiguous amino acids of SEQ ID NO:42, and at least 10 contiguous amino acids of SEQ ID NO:44.
 10. The isolated and purified subgenomic polynucleotide of claim 9 which encodes an amino acid sequence selected from the group consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and
 44. 11. The isolated and purified subgenomic polynucleotide of claim 10 wherein the nucleotide sequence is selected from the group consisting of SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 31, 33, 35, 37, 39, 41, and
 43. 12. An isolated and purified subgenomic polynucleotide comprising a polynucleotide segment which hybridizes to a nucleotide sequence selected from the group consisting of SEQ ID NOS:1, 3, 5 ,7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 31, 33, 35, 37, 39, 41, and 43, and the complements thereof after washing with 0.2×SSC at 65° C., wherein the polynucleotide segment encodes a protein having an amino acid sequence selected from the group consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and
 44. 13. An isolated and purified subgenomic polynucleotide comprising a nucleotide sequence selected from the group consisting of at least 499 contiguous nucleotides of SEQ ID NO:1, at least 1141 contiguous nucleotides of SEQ ID NO:1, at least 475 contiguous nucleotides of SEQ ID NO:3, at least 313 contiguous nucleotides selected from nucleotides 1-1001 of SEQ ID NO:3, at least 751 contiguous nucleotides of SEQ ID NO:5, at least 538 contiguous nucleotides of SEQ ID NO:5, at least 11 contiguous nucleotides selected from nucleotides 1-946 of SEQ ID NO:5, at least 13 contiguous nucleotides selected from nucleotides 1-1039 of SEQ ID NO:5, at least 651 contiguous nucleotides of SEQ ID NO:7, at least 522 contiguous nucleotides of SEQ ID NO:7, at least 11 contiguous nucleotides selected from nucleotides 1-913 of SEQ ID NO:7, at least 484 contiguous nucleotides of SEQ ID NO:9, at least 317 contiguous nucleotides of SEQ ID NO:9, at least 11 contiguous nucleotides selected from nucleotides 1-216 of SEQ ID NO:9, at least 11 contiguous nucleotides selected from nucleotides 379-812 of SEQ ID NO:9, at least 183 contiguous nucleotides selected from nucleotides 1-984 of SEQ ID NO:9, at least 594 contiguous nucleotides of SEQ ID NO:11, at least 289 contiguous nucleotides of SEQ ID NO:11, at least 11 contiguous nucleotides selected from nucleotides 1-585 of SEQ ID NO:11, at least 11 contiguous nucleotides selected from nucleotides 853-1120 of SEQ ID NO:11, at least 592 contiguous nucleotides of SEQ ID NO:13, at least 275 contiguous nucleotides of SEQ ID NO:13, at least 11 contiguous nucleotides selected from nucleotides 1-294 of SEQ ID NO:13, at least 537 contiguous nucleotides of SEQ ID NO:15, at least 294 contiguous nucleotides selected from nucleotides 1-1889 of SEQ ID NO:15, at least 171 contiguous nucleotides selected from nucleotides 318-1766 of SEQ ID NO:15, at least 11 contiguous nucleotides selected from nucleotides 1-42 of SEQ ID NO:15, at least 11 contiguous nucleotides selected from nucleotides 478-908 of SEQ ID NO:15, at least 11 contiguous nucleotides selected from nucleotides 1059-1078 of SEQ ID NO:15, at least 205 contiguous nucleotides of SEQ ID NO:17, at least 440 contiguous nucleotides of SEQ ID NO:19, at least 451 contiguous nucleotides of SEQ ID NO:21, at least 11 contiguous nucleotides selected from nucleotides 1-121 of SEQ ID NO:21, at least 11 contiguous nucleotides selected from nucleotides 474-592 of SEQ ID NO:21, at least 351 contiguous nucleotides of SEQ ID NO:23, at least 21 contiguous nucleotides selected from nucleotides 1-1943 of SEQ ID NO:23, at least 11 contiguous nucleotides selected from 1-612 of SEQ ID NO:23, at least 11 contiguous nucleotides selected from nucleotides 611-719 of SEQ ID NO:23, at least 11 contiguous nucleotides selected from nucleotides 713-830 of SEQ ID NO:23, at least 11 contiguous nucleotides selected from nucleotides 830-1933 of SEQ ID NO:23, at least 492 nucleotides of SEQ ID NO:25, at least 11 contiguous nucleotides selected from nucleotides 758-847 of SEQ ID NO:25, at least 1024 contiguous nucleotides of SEQ ID NO:27, at least 347 contiguous nucleotides of SEQ ID NO:29, at least 11 contiguous nucleotides selected from nucleotides 548-601 of SEQ ID NO:29, at least 394 contiguous nucleotides of SEQ ID NO:31, at least 11 contiguous nucleotides selected from nucleotides 1-361 of SEQ ID NO:31, at least 11 contiguous nucleotides selected from nucleotides 1083-1102 of SEQ ID NO:31, at least 492 contiguous nucleotides of SEQ ID NO:33, at least 510 contiguous nucleotides of SEQ ID NO:35, at least 11 contiguous nucleotides selected from nucleotides 1-502 or 505-631 of SEQ ID NO:35, at least 392 contiguous nucleotides of SEQ ID NO:37, at least 11 contiguous nucleotides selected from nucleotides 1-502 of SEQ ID NO:37, at least 11 contiguous nucleotides selected from nucleotides 505-631 of SEQ ID NO:37, at least 559 contiguous nucleotides of SEQ ID NO:39, at least 11 contiguous nucleotides selected from nucleotides 1-92 of SEQ ID NO:39, at least 254 contiguous nucleotides of SEQ ID NO:41, at least 11 contiguous nucleotides selected from nucleotides 1-34 of SEQ ID NO:41 at least 11 contiguous nucleotides selected from nucleotides 55-110 of SEQ ID NO:41, at least 103 contiguous nucleotides of SEQ ID NO:43, at least 11 contiguous nucleotides selected from nucleotides 1-280 of SEQ ID NO:43, at least 11 contiguous nucleotides selected from nucleotides 270-319 of SEQ ID NO:43, at least 11 contiguous nucleotides selected from nucleotides 378-423 of SEQ ID NO:43, at least 11 contiguous nucleotides selected from nucleotides 414-492 of SEQ ID NO:43, at least 11 contiguous nucleotides selected from nucleotides 532-570 of SEQ ID NO:43, at least 11 contiguous nucleotides selected from nucleotides 1086-1152 of SEQ ID NO:43, and the complements thereof.
 14. A construct comprising the isolated and purified subgenomic polynucleotide of claim
 9. 15. The construct of claim 14 further comprising a promoter which is operatively linked to the nucleotide sequence.
 16. A host cell comprising the construct of claim
 14. 17. The host cell of claim 16 which is a mammalian cell.
 18. A process for producing a protein, comprising the steps of: growing a culture of the host cell of claim 66 in a suitable culture medium; and purifying the protein secreted from the host cell.
 19. A polynucleotide array comprising at least one single-stranded polynucleotide which comprises at least 12 contiguous nucleotides of a nucleotide sequence selected from the group consisting of SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, and
 43. 20. A method of detecting differential gene expression between two biological samples, comprising the step of: contacting a first biological sample comprising single-stranded polynucleotide molecules with a first polynucleotide array comprising at least one single-stranded polynucleotide which comprises at least 12 contiguous nucleotides of a nucleotide sequence selected from the group consisting of SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, and43; contacting a second biological sample comprising single-stranded polynucleotide molecules with a second polynucleotide array, wherein the first and second polynucleotide arrays comprise identical single-stranded polynucleotides; and detecting a first and second pattern of double-stranded polynucleotides bound to the first and second polynucleotide arrays, wherein a difference between the first and second patterns indicates a gene which is differentially expressed between the first and second biological samples.
 21. The method of claim 20 wherein the first biological sample is suspected of being diseased and wherein the second biological sample is not diseased. 